Systems, devices, and methods for organ retroperfusion along with regional mild hypothermia

ABSTRACT

A quick-connector for use with an autoretroperfusion and hypothermia system and methods of using the connector. The connector comprises a coolant inlet, a coolant outlet, a coolant reservoir, a blood lumen outlet, a blood lumen inlet, and a blood lumen, whereby the coolant outlet is configured to accept a cooling product from the reservoir, the reservoir is configured to accept cooling product from the coolant inlet. Flowing blood powered by the patient&#39;s heart may enter the connector through the blood lumen inlet, travel through the blood lumen while being cooled by cooling product in the reservoir, and leave the connector through the blood lumen outlet. The temperature of blood leaving the connector can be measured at the blood lumen outlet. Catheters can be attached to the blood lumen inlet and blood lumen outlet to receive and send blood, respectively. A cooling system can be attached to the coolant inlet and coolant outlet to provide a source of cooling product.

RELATED APPLICATIONS

The present application is also related to, claims the priority benefit of, and is a U.S. continuation application of, U.S. patent application Ser. No. 15/943,036, filed Apr. 2, 2018 and issued as U.S. Pat. No. 11,045,300 on Jun. 29, 2021, which is (a) related to, claims the priority benefit of U.S. Provisional Patent Application Ser. No. 62/542,691, filed Aug. 8, 2017; (b) related to, claims the priority benefit of U.S. Provisional Patent Application Ser. No. 62/479,373, filed Mar. 31, 2017; and (c) related to, claims the priority benefit of, and is a U.S. continuation-in-part (CIP) patent application of, U.S. patent application Ser. No. 15/363,377, filed Nov. 29, 2016, which is related to, claims the priority benefit of, and is a U.S. continuation application of, U.S. patent application Ser. No. 14/093,300, filed Nov. 29, 2013 and issued as U.S. Pat. No. 9,504,781 on Nov. 29, 2016, which is (a) related to, and claims the priority benefit of, U.S. Provisional Patent Application Ser. No. 61/731,235, filed Nov. 29, 2012; and (b) is related to U.S. patent application Ser. No. 13/965,533, filed Aug. 13, 2013, which (i) is related to, and claims the priority benefit of, U.S. Provisional Patent Application Ser. No. 61/682,348, filed Aug. 13, 2012, (ii) is related to, claims the priority benefit of, and is a U.S. continuation in part of, U.S. patent application Ser. No. 13/646,094, filed Oct. 5, 2012 and issued as U.S. Pat. No. 8,968,230 on Mar. 3, 2015, which (A) is related to, and claims the priority benefit of, U.S. Provisional Patent Application Ser. No. 61/543,330, filed Oct. 5, 2011, and (B) is related to, claims the priority benefit of, and is a continuation-in-part application of, U.S. patent application Ser. No. 13/221,514, filed Aug. 30, 2011 and issued as U.S. Pat. No. 8,945,039 on Feb. 3, 2015, which is related to, claims the priority benefit of, and is a continuation-in-part application of, U.S. patent application Ser. No. 13/092,803, filed Apr. 22, 2011 and issued as U.S. Pat. No. 8,888,733 on Nov. 18, 2014, which is related to, claims the priority benefit of, and is a continuation-in-part application of, U.S. patent application Ser. No. 13/125,512, filed Apr. 21, 2011 and issued as U.S. Pat. No. 8,979,786 on Mar. 17, 2015, which is related to, claims the priority benefit of, and is a § 371 national stage entry of, International Patent Application Serial No. PCT/US2008/087863, filed Dec. 19, 2008, and (iii) is related to, claims the priority benefit of, and is a continuation-in-part application of, U.S. patent application Ser. No. 13/221,514, filed Aug. 30, 2011 and issued as U.S. Pat. No. 8,945,039, which is related to, claims the priority benefit of, and is a continuation-in-part application of, U.S. patent application Ser. No. 13/092,803, filed Apr. 22, 2011 and issued as U.S. Pat. No. 8,888,733 on Nov. 18, 2014, which is related to, claims the priority benefit of, and is a continuation-in-part application of, U.S. patent application Ser. No. 13/125,512, filed Apr. 21, 2011 and issued as U.S. Pat. No. 8,979,786 on Mar. 17, 2015, which is related to, claims the priority benefit of, and is a § 371 national stage entry of, International Patent Application Serial No. PCT/US2008/087863, filed Dec. 19, 2008. The contents of each of these applications and patents are hereby incorporated by reference in their entirety into this disclosure.

BACKGROUND

While direct surgical and percutaneous revascularization through procedures such as a percutaneous transluminal coronary angioplasty (“PTCA”) or coronary artery bypass grafting (“CABG”) remain the mainstay of treatment for patients with angina and coronary artery disease (“CAD”), there are many patients that are not amenable to such conventional revascularization therapies. Because of this, much effort has been made to find alternative methods of revascularization for ischemic cardiac patients who are not candidates for revascularization by conventional techniques. Such patients are generally identified as “no-option” patients because there is no conventional therapeutic option available to treat their condition. As described in detail herein, the present disclosure provides various embodiments of devices to address such chronic conditions.

In addition, and as described in detail herein, the present disclosure provides various embodiments of devices that can be used acutely to treat patients with a number of conditions, such as S-T segment elevated myocardial infarction (STEMI) or cardiogenic shock or patients who require high risk percutaneous coronary intervention, until they can receive more traditional therapy.

Currently, there are multiple specific conditions for which conventional revascularization techniques are known to be ineffective as a treatment. Two specific examples of such cardiac conditions include, without limitation, diffuse CAD and refractory angina. Furthermore, a percentage of all patients diagnosed with symptomatic CAD are not suitable for CABG or PTCA. In addition and for various reasons discussed below, diabetic patients—especially those with type 2 diabetes—exhibit an increased risk for CAD that is not effectively treated by conventional revascularization techniques.

There is currently little data available on the prevalence and prognosis of patients with symptomatic CAD that is not amenable to revascularization through conventional methods. However, one study indicated that out of five hundred (500) patients with symptomatic CAD who were considering direct myocardial revascularization and angiogenesis, almost twelve percent (12%) were not suitable for CABG or PTCA for various reasons. Furthermore, in general, patients with atherosclerotic involvement of the distal coronary arteries have high mortality and morbidity. For example, a study conducted on patients indicated that, one (1) year after being diagnosed with atherosclerotic involvement of the distal coronary arteries, 39.2% of such patients had a cardiac-related death, 37.2% had an acute myocardial infarction, and 5.8% had developed congestive heart failure. Overall, 82.2% of the patients with atherosclerotic involvement of distal coronary arteries had developed or experienced a significant cardiac event within one (1) year.

A. Diffuse CAD and Refractory Angina

CAD is typically not focal (i.e. limited to one point or a small region of the coronary artery), but rather diffused over a large length of the entire vessel, which is termed “diffuse CAD.” Several studies indicate that patients with a diffusely diseased coronary artery for whom standard CABG techniques cannot be successfully performed constitute about 0.8% to about 25.1% of all patients diagnosed with CAD. Furthermore, it is believed that diffuse CAD is much more common than conventionally diagnosed because it is often difficult to detect by an angiogram due to the two-dimensional views.

Practitioners have realized that the quality of a patient's distal coronary arteries is one of the critical factors related to a successful outcome of a surgical revascularization. As previously indicated, there is considerable evidence that CABG for vessels having diffuse CAD results in a relatively poor outcome. In fact, studies have indicated that diffuse CAD is a strong independent predictor of death after a CABG procedure. Further, as previously noted conventional revascularization techniques have also proven ineffective on a subgroup of patients with medically refractory angina. In line with the aforementioned reasoning, this is likely because patients with medically refractory angina have small or diffusely diseased distal vessels that are not amenable to conventional revascularization therapies. Accordingly, patients exhibiting diffuse CAD or medically refractory angina are often considered no-option patients and not offered bypass surgery, PTCA, or other conventional procedures.

B. Diabetes as a Risk Factor

Diabetes is an important risk factor for the development of CAD, diffuse or asymptomatic, and it has been estimated that approximately seventy-five percent (75%) of the deaths in diabetic patients are likely attributed to CAD. It is estimated that 16 million Americans have diabetes, without only 10 million being diagnosed. Patients with diabetes develop CAD at an accelerated rate and have a higher incidence of heart failure, myocardial infarction, and cardiac death than non-diabetics.

According to recent projections, the prevalence of diabetes in the United States is predicted to be about ten percent (10%) of the population by 2025. Further, the increasing prevalence of obesity and sedentary lifestyles throughout developed countries around the world is expected to drive the worldwide number of individuals with diabetes to more than 330 million by the year 2025. As may be expected, the burden of cardiovascular disease and premature mortality that is associated with diabetes will also substantially increase, reflecting in not only an increased amount of individuals with CAD, but an increased number of younger adults and adolescents with type 2 diabetes who are at a two- to four-fold higher risk of experiencing a cardiovascular-related death as compared to non-diabetics.

In addition to developing CAD at an accelerated rate, CAD in diabetic patients is typically detected in an advanced stage, as opposed to when the disease is premature and symptomatic. Consequently, when diabetic patients are finally diagnosed with CAD they commonly exhibit more extensive coronary atherosclerosis and their epicardial vessels are less amendable to interventional treatment, as compared to the non-diabetic population. Moreover, as compared with non-diabetic patients, diabetic patients have lower ejection fractions in general and therefore have an increased chance of suffering from silent myocardial infarctions.

C. No-Option Patients

Some studies have shown that two-thirds (⅔rds) of the patients who were not offered bypass surgery, because of diffuse CAD or otherwise, either died or had a non-fatal myocardial infarction within twelve (12) months. Furthermore, patients diagnosed with diffuse CAD ran a two-fold increased risk of in-hospital death or major morbidity, and their survival rate at two (2) years was worse than those patients who exhibited non-diffuse CAD or other complicating conditions. As previously indicated, the majority of these patients are considered no-option patients and are frequently denied bypass surgery as it is believed that CABG would result in a poor outcome.

Due to the increasing numbers of no-option patients and a trend in cardiac surgery towards more aggressive coronary interventions, a growing percentage of patients with diffuse CAD and other no-option indications are being approved for coronary bypass surgery because, in effect, there are no other meaningful treatment or therapeutic options. Some effects of this trend are that the practice of coronary bypass surgery has undergone significant changes due to the aggressive use of coronary stents and the clinical profiles of patients referred for CABG are declining. As such, performing effective and successful coronary bypass surgeries is becoming much more challenging. Bypass grafting diffusely diseased vessels typically requires the use of innovative operations such as on-lay patches, endarterectomies and more than one graft for a single vessel. Patients with “full metal jackets” (or multiple stents) are typically not referred to cardiac surgeons and often end up as no-option patients despite the attempts of using these innovative surgeries.

In recent decades, the spectrum of patients referred for CABG are older and are afflicted with other morbidities such as hypertension, diabetes mellitus, cerebral and peripheral vascular disease, renal dysfunction, and chronic pulmonary disease. In addition, many patients referred for CABG have advanced diffuse CAD and have previously undergone at least one catheter-based intervention or surgical revascularization procedure that either failed or was not effective. Because of this, the patient's vessels may no longer be graftable and complete revascularization using conventional CABG may not be feasible. An incomplete myocardial revascularization procedure has been shown to adversely affect short-term and long-term outcomes after coronary surgery.

Due in part to some of the aforementioned reasons, reoperative CABG surgery is now commonplace, accounting for over twenty percent (20%) of cases in some clinics. It is well established that mortality for reoperative CAB G operations is significantly higher than primary operations. As such, the risk profile of reoperative patients is significantly increased and such patients are subjected to an increased risk of both in-hospital and long-term adverse outcomes.

Further, clinicians have also turned to unconventional therapies to treat non-option patients. For example, coronary endarterectomy (“CE”) has been used as an adjunct to CABG in a select group of patients with diffuse CAD in order to afford complete revascularization. However, while CE was first described in 1957 as a method of treating CAD without using cardiopulmonary bypass and CABG, this procedure has been associated with high postoperative morbidity and mortality rates and has been afforded much scrutiny. Nevertheless, CE is the only therapeutic option available for many no-option patients with diffuse CAD.

Similarly, because conventional therapies have proven ineffective or are unavailable to high risk patients, perioperative transmyocardial revascularization (“TMR”) has been indicated for patients suffering from medically refractory angina. TMR has proven effective for most patients suffering from refractory angina; the mortality rate after TMR in patients with stable angina ranges between about one to twenty percent (1-20%). Furthermore, in one study, TMR resulted in a higher perioperatively mortality rate in patients with unstable angina than those with stable angina (27% versus 1%). Some even report an operative mortality rate as low as twelve percent (12%). Patients who experience angina and who cannot be weaned from intravenous nitroglycerin and heparin have a significantly higher operative mortality rate (16-27% versus 1-3%). Based on these findings, the clinical practice has been to avoid taking such patients to the operating room for TMR if at all possible. The success of TMR is thought to be due to improved regional blood flow to ischemic myocardium, but the precise mechanisms of its effects remain unclear.

D. Acute Applications

When a coronary artery becomes blocked, the flow of blood to the myocardium stops and the muscle is damaged. This process is known as myocardial infarction (MI). An MI can damage the myocardium, resulting in a scarred area that does not function properly. MI has an annual incidence rate of 1.5 million in the US and is the primary driver of roughly 500,000 cases of mortality and high morbidity rates in CAD patients. Immediate reperfusion of the myocardium following MI is clinically desirable to preserve as much heart tissue as possible. Current revascularization options include thrombolytic medications, percutaneous coronary intervention (PCI), or coronary artery bypass graft (CABG). While thrombolytic compounds can be administered swiftly in an acute care facility, the vast majority of MI patients require a PCI or CABG to adequately restore reliable blood flow to the heart tissue. Both of these revascularization techniques are clinically safe and effective, however, they require specialized staff and facilities, which are not available at all acute care facilities, or not available soon enough to preserve enough myocardial tissue in the wake of an MI. A significant effort has been undertaken in recent years to speed MI patients to the cath lab for PCI upon presenting, but these programs are not available everywhere, and even where available, do not often meet the 90 minute target of door to balloon time.

In the US, nearly 75,000 CAD patients annually present with atherosclerosis of the left main coronary artery (LMCA). The LMCA delivers oxygenated blood to 75% or more of the myocardium. An untreated, diseased LMCA results in 20% 1-year and 50% 7- to 10-year mortality rates. Historically, PCI of the LMCA (LMPCI) has been deemed too risky, however, recent advances in technique and tools have begun to allow an expanded LMCA patient population for PCI, especially in certain patient conditions where PCI is preferable to CABG (e.g., patients who are aging, delicate, and/or in critical condition).

The risks of LMPCI include prolonged myocardial ischemia from balloon inflations, “no-reflow phenomenon” (2-5% incidence rate), or coronary artery dissections (30% incidence rate). Existing circulatory support devices used to address these hemodynamic issues, such as the intra-aortic balloon pump (IABP) and left ventricle circulatory support devices (e.g., Impella 2.5), are unable to sufficiently meet the myocardium oxygen demands even though cardiac pumping mechanics are improved. The assistance from these devices is limited further during no-reflow and coronary artery dissection events. In addition, the clinically superior left ventricle circulatory support devices are complicated to use and require dedicated training and facilities, which has prevented wide-spread clinical adoption.

There are over 35,000 cardiogenic shock (CS) patients each year in the US. This condition severely complicates an MI event with in-hospital mortality rates exceeding 50 percent. PCI is the standard of care for these acute patients; however, the CS patient must be stabilized prior to intervention, according to ACC/AHA guidelines, using a short-term circulatory support device as a bridge. An IABP or left ventricle circulatory support device (e.g. Impella 2.5) can currently be utilized in these cases to stabilize the heart while awaiting revascularization.

The 200,000 S-T segment elevated MI (STEMI) patients per year in the US require immediate reperfusion of the myocardium. Thrombolytic medications are administered as the primary revascularization technique, however, 70 percent of those receiving thrombolysis fail to respond. Furthermore, 10 percent of those that initially respond to thrombolysis experience reocclusion while still an in-patient. These STEMI patients require clinically superior rescue PCI, as opposed to repeated thrombolysis.

Because only 1,200 out of 5,000 acute care hospitals are capable of performing PCI (and even fewer are capable of CABG), nearly 60 percent of STEMI patients do not achieve the required 90 minute time-frame for revascularization.

While awaiting revascularization, IAPB currently is the preferred circulatory assist device and is indicated for use by critical care unit (CCU), intensive care unit (ICU) and emergency medicine (ER) physicians in a variety of clinical settings. However, the IABP's use in MI events remains at less than 5 percent of cases due to complicated training and device-related malfunctions in 12-30% of all cases.

Circulatory support devices used in these cases have two major problems: inability to adequately augment blood flow in flow-limiting atherosclerotic coronary arteries to a damaged myocardium, and 12-30% device complication incidence rates, including peripheral ischemia, compartment syndrome, infection, hematological issues, and mechanical issues.

Peripheral artery disease (PAD) affects approximately eight million Americans (12-20% age 65 and older) and is associated with significant morbidity and mortality. Despite the advances in peripheral arterial revascularization, there remains a large group of patients who cannot be helped by conventional surgical techniques due to severe diffuse occlusion of the distal arterial tree. These patients almost inevitably require major amputation due to gangrene, ulceration, severe pain at rest, or a combination of these (Stage IV Fontaine).

The incidence of critical leg ischemia worldwide has been estimated to range from 500 to 1,000 per one million persons per year. A Swedish study based on a longitudinal analysis of 321 patients identified a mean number of three surgical interventions per patient and a mean length of hospitalization of 117 days, resulting in significant health care costs and disruption of patient's lives.

The current therapeutic options to salvage ischemic limbs include open surgery and radiologic transcatheter therapies such as thrombolysis, angioplasty, and thrombectomy. One approach advocates initial treatment with mechanical transcatheter thrombectomy along with one of several available devices, hydrolyser, or rapid debulking of thrombus. This may be followed by low-dose, short-duration local thrombolytic therapy. Any residual underlying stenoses may then be treated with angioplasty and stent placement or with open surgery.

Despite such an optimized approach, a subgroup of patients (approximately 14%-20%) is not suited for distal arterial reconstruction and may require amputation. Few effective therapeutic options are available to these patients, who usually suffer from advanced disease of small vessels of the calf and foot and who may be further compromised by other co-morbidities.

The clinical prognosis for patients who present with critical leg ischemia is poor. Despite the extensive use of endovascular and surgical revascularization procedures, the primary amputation rate for critical leg ischemia varies from 10% to 40%. The total estimated number of major amputations performed in patients with critical leg ischemia is about 250 to 500 per one million persons per year in Europe and about 280 per one million persons per year in the US. The perioperative mortality for major amputation in these patients is about 10%. Within two years, 30% of patients who undergo below-knee amputation will die, 15% will require a contralateral major amputation, and another 15% will require above-knee amputation. Clearly, there is a need to reduce the number of amputations in this subgroup of patients, who present with critical leg ischemia and are beyond current therapy.

In view of the same, devices and methods to facilitate venous arterialization in the periphery, using minimally invasive surgical techniques and percutaneous procedures, would be well received in the marketplace.

ST segment elevation myocardial infarction (STEMI) is the most severe form of acute coronary syndrome (ACS) that affects nearly 500,000 Americans each year and places a heavy clinical and financial burden on the healthcare system. STEMI treatment requires prompt reperfusion to limit myocardial injury (recommended time of less than 90 minutes from hospital arrival to therapy delivery or 90-minute door to balloon time) and significantly contributes to the $31B annual U.S. cost for treatment of acute myocardial infarction (AMI).

Mortality following STEMI is directly related to the extent of the total myocardial injury. Minimization of myocardial injury is best accomplished with reperfusion via percutaneous coronary intervention (PCI). Even after PCI, the myocardium can experience additional injury, however, directly related to the restoration of blood flow directly following ischemia (termed reperfusion injury or RI). RI and no-reflow phenomenon (microvascular obstruction) occur in at least 60% of all STEMI patients following PCI and lead to multiple complications including increased infarct size (up to 50% of the total infarct area), diminished left ventricular (LV) function, LV remodeling, and increased mortality. Due to the magnitude and severity of RI, numerous therapies have been investigated, such as pharmacologics and ischemic pre- and post-conditioning (IP). These therapies are fundamentally limited, however, mainly because they cannot be effectively delivered to the ischemic myocardium prior to PCI due to the arterial obstruction (i.e., the arterial obstruction does not allow for arterial therapy delivery to the region of interest until PCI is completed, which would be too late to prevent RI). Thus, novel approaches are needed to limit RI without first requiring opening of the arterial obstruction.

BRIEF SUMMARY

In at least one embodiment of a system of the present disclosure, the system comprises a hypothermia system comprising a hypothermia system outlet and a hypothermia system inlet; and a connector comprising a coolant inlet, a coolant outlet, a coolant reservoir, and a blood lumen, whereby the coolant inlet is configured to couple to the hypothermia system outlet and whereby the coolant outlet is configured to couple to the hypothermia system inlet; whereby a cooling product, when the hypothermia system is connected to the connector, can flow from the hypothermia system, through the hypothermia system outlet, into the coolant inlet, through the coolant reservoir, into the coolant outlet, and into the hypothermia system inlet, so that the cooling product can cool blood flowing through the blood lumen.

In at least one embodiment of a system of the present disclosure, the connector further comprises a blood inlet configured to connect to a first catheter; and a blood outlet configured to connect to a second catheter; whereby the blood can flow from the first catheter, into the blood inlet, through the blood lumen, into the blood outlet, and into the second catheter. In at least one embodiment of a system of the present disclosure, the system further comprises the first catheter. In at least one embodiment of a system of the present disclosure, the first catheter has a fenestration pattern comprising a plurality of fenestration apertures proximal to a distal end of the first catheter. In at least one embodiment of a system of the present disclosure, the first catheter comprises a balloon configured for inflation, the balloon located proximal to the plurality of fenestration apertures. In at least one embodiment of a system of the present disclosure, the first catheter comprises an atraumatic tip at the distal end.

In at least one embodiment of a system of the present disclosure, the first catheter comprises a first segment adjacent to a second segment, the second segment having a smaller diameter than the first segment. In at least one embodiment of a system of the present disclosure, the first catheter comprises a first segment adjacent to a second segment, the second segment having a smaller diameter than the first segment. In at least one embodiment of a system of the present disclosure, the first catheter further comprises a third segment adjacent to the second segment, the third segment having a smaller diameter than the second segment. In at least one embodiment of a system of the present disclosure, the first catheter further comprises a fourth segment adjacent to the third segment, the fourth segment having a smaller diameter than the third segment.

In at least one embodiment of a method of the present disclosure, the method comprises the steps of introducing at least a portion of the system of the present disclosure into a mammalian patient; connecting the first catheter to the blood inlet and connecting the second catheter to the blood outlet so that the blood can flow from the first catheter, into the blood inlet, through the blood lumen, into the blood outlet, and into the second catheter; connecting the coolant inlet to the hypothermia system outlet and connecting the coolant outlet to the hypothermia system outlet; and operating the hypothermia system so that the cooling product can flow from the hypothermia system, through the hypothermia system outlet, into the coolant inlet, through the coolant reservoir, into the coolant outlet, and into the hypothermia system inlet, so that the cooling product can cool the blood flowing through the blood lumen. In at least one embodiment of a method of the present disclosure, the second catheter is positioned within the mammalian patient so to deliver the blood cooled from the operating step to a heart of the patient to reduce a temperature of the heart. In at least one embodiment of a method of the present disclosure, the method is performed to reduce a size of a myocardial infarct of the heart. In at least one embodiment of a method of the present disclosure, the method further comprises the step of ceasing operation of the hypothermia system when a desired temperature of the heart has been achieved.

In various catheters, cannulas, systems, kits and/or methods of the present disclosure, the catheters, cannulas, systems, and/or kits comprising the same and/or components of the same, further comprise a regional hypothermia system of the present disclosure operably coupled thereto, the regional hypothermia system operable to reduce and/or regulate the temperature of a fluid flowing therethrough, such as blood, and/or operable to reduce and/or regulate the temperature of a vessel, a tissue, and/or an organ at or near the blood. In other embodiments, the regional hypothermia system comprises a heat exchanger configured to reduce and/or regulate the temperature of the fluid. In various embodiments, one or more components of the regional hypothermia system uses a cooling product to reduce and/or regulate the temperature of the fluid. In any number of embodiments, the devices further comprise one or more temperature sensors coupled thereto, the one or more temperature sensors operable to detect a temperature of the blood, the vessel, the tissue, and/or the organ. In various embodiments, the devices further comprise a remote module in wired or wireless communication with the one or more temperature sensors, the remote module operable to and configured to receive the detected temperature(s) and process the same to regulate, reduce, and/or increase the temperature of the blood, the vessel, the tissue, and/or the organ by way of altering the operation of the regional hypothermia system.

In at least one embodiment of a hypothermia kit of the present disclosure, the hypothermia kit comprises a regional hypothermia system of the present disclosure, and a catheter, cannula, system, and/or kit comprising the same and/or components of the same. In various embodiments, the hypothermia kit is useful to treat a condition of a mammalian tissue and/or organ by way of reducing blood, other fluid, tissue, and/or organ temperature and/or regulating the temperature of the same.

In at least one embodiment of a method of organ perfusion (a perfusion method) of the present disclosure, the method comprises the steps of positioning at least part of a first catheter having a cannula within an artery of a patient, the first catheter configured to permit arterial blood to flow therethrough and further configured to permit a portion of the arterial blood to flow through the cannula, positioning at least part of a second catheter within a vein of the patient at or near a target organ, the second catheter configured to receive some or all of the portion of the arterial blood, connecting the cannula of the first catheter to a portion of the second catheter so that some or all of the portion of the arterial blood flowing through the cannula is provided into the vein to treat a condition or disease of the target organ, and reducing and/or regulating a temperature of blood flowing through the cannula using a regional hypothermia system operably coupled to the cannula. In another embodiment, the step of connecting the cannula to the portion of the second catheter is performed to permit blood flow from the cannula to the vein to treat a cardiac condition. In yet another embodiment, the step of reducing and/or regulating a temperature of blood flowing through the cannula is performed to treat a cardiac condition.

In at least one embodiment of a method of organ perfusion (a perfusion method) of the present disclosure, the method comprises the steps of positioning at least a portion of an arterial tube of a perfusion system within an artery of a patient, the arterial tube configured to permit arterial blood to flow therethrough, positioning at least a portion of a first catheter of the perfusion system into a vein of the patient at or near a target organ, the first catheter configured to receive some or all of the arterial blood from the arterial tube, operating a first flow regulator of the perfusion system so that some or all of the arterial blood flowing through the arterial tube is provided into the vein to treat a condition or disease of the target organ, reducing and/or regulating a temperature of blood flowing through the arterial tube using a regional hypothermia system operably coupled to the arterial tube. In another embodiment, the step of positioning at least part of the arterial tube is performed by positioning at least part of the arterial tube within an artery selected from the group consisting of a femoral artery, an internal femoral artery, an iliac artery, an axillary artery, a brachial artery, a subclavian artery, an epigastric artery, and an external carotid artery. In yet another embodiment, the step of operating a first flow regulator is performed to permit blood flow from the cannula to the vein to treat a cardiac condition. In an additional embodiment, the step of positioning at least a portion of a first catheter further comprises the step of inflating an expandable balloon positioned along the portion of the first catheter positioned in the vein to secure the portion of the first catheter within the vein. In yet an additional embodiment, the step of positioning at least a portion of an arterial tube further comprises the step of operating the first flow regulator to regulate blood flow from the artery to the vein prior to the step of positioning at least a portion of a first catheter so to substantially eliminate an introduction of a gas within at least a portion of the perfusion system to the vein.

In at least one embodiment of a method of organ perfusion (a perfusion method) of the present disclosure, the method further comprises the step of removing the at least a portion of a first catheter from the vein after an elapsed period of time after positioning the at least a portion of a first catheter into the vein, the elapsed period of time selected from the group consisting of within about 24 hours, between about 24 hours and about 48 hours, and after about 48 hours. In an additional embodiment, the step of operating a first flow regulator of the perfusion system is performed to control blood pressure to limit potential injury to the vein of the patient. In yet an additional embodiment, the step of positioning at least a portion of a first catheter is performed to position the first catheter at a location so not to impede coronary venous return. In another embodiment, the method further comprises the step of temporarily deflating the expandable balloon during operation of the system to alleviate a localized increase in pressure or edema at or near the expandable balloon. In yet another embodiment, the step of reducing and/or regulating a temperature of blood flowing through the arterial tube is performed to treat a cardiac condition.

In at least one embodiment of a catheter for controlling blood perfusion pressure (a perfusion catheter) of the present disclosure, the catheter comprises an elongated body configured for placement within an artery, the elongated body having a proximal open end, a distal open end, and at least one lumen extending between the proximal open end and the distal open end, a cannula configured to extend through an opening in the artery, the cannula comprising a hollow interior in fluid communication with at least one of the at least one lumens of the elongated body, and a regional hypothermia system operably coupled to the catheter, the regional hypothermia system operable to reduce and/or regulate a temperature of a bodily fluid flowing through the catheter, the catheter configured so that when the proximal open end and the distal open end are each positioned within the artery, blood flowing through the artery is not substantially inhibited by the elongated body. In another embodiment, the hollow interior of the cannula comprises a first diameter, the at least one lumen comprises a second diameter and the first diameter is less than the second diameter. In yet another embodiment, the cannula extends from the elongated body such that an angle is formed between the cannula and the elongated body, and wherein the cannula is movable between a substantially extended configuration wherein the angle comprises between about 15° and about 90° and a substantially collapsed configuration wherein the angle comprises less than about 15°. In an additional embodiment, the regional hypothermia system comprises a heat exchanger configured to reduce and/or regulate the temperature of the bodily fluid. In yet an additional embodiment, one or more components of the regional hypothermia system uses a cooling product to reduce and/or regulate the temperature of the bodily fluid.

In at least one embodiment of a catheter for controlling blood perfusion pressure (a perfusion catheter) of the present disclosure, the catheter further comprises one or more temperature sensors coupled to the catheter, the one or more temperature sensors operable to detect the temperature of the bodily fluid. In another embodiment, the regional hypothermia system further comprises a remote module in wired or wireless communication with the one or more temperature sensors, the remote module operable to and configured to receive the detected temperature(s) and process the same to regulate, reduce, and/or increase the temperature of the bodily fluid by way of altering an operation of the regional hypothermia system.

In an embodiment of a connector for use with an autoretroperfusion and hypothermia system, the connector comprises: a blood lumen inlet, a blood lumen outlet, and a blood lumen extending therebetween; a coolant inlet for receiving a cooling product; a reservoir for receiving the cooling product from the coolant inlet and cooling a blood flowing through the blood lumen; and a coolant outlet for receiving the cooling product from the reservoir and sending the cooling product out of the connector.

In an alternate embodiment of a connector for use with an autoretroperfusion and hypothermia system, blood flowing through the blood lumen is pumped solely by a patient's own heart. In an alternate embodiment of a connector for use with an autoretroperfusion and hypothermia system, the blood is flowing through the blood lumen without use of an outside pump.

In an alternate embodiment of a connector for use with an autoretroperfusion and hypothermia system, the blood lumen is defined within the reservoir. In another embodiment, the reservoir is immediately adjacent the blood lumen.

In an alternate embodiment of a connector for use with an autoretroperfusion and hypothermia system, the blood lumen inlet and the coolant inlet are positioned at a first end of the connector; and the blood lumen outlet and the coolant outlet are positioned at a second end of the connector such that the cooling product and the blood flowing through the blood lumen flow in a parallel direction.

In an alternate embodiment of a connector for use with an autoretroperfusion and hypothermia system, the blood lumen inlet and the blood lumen outlet comprise luer lock connections.

In an alternate embodiment of a connector for use with an autoretroperfusion and hypothermia system, the connector comprises a 6 French diameter and 30 cm long flexible tubing.

In an alternate embodiment of a connector for use with an autoretroperfusion and hypothermia system, the connector also comprises a noncontact temperature sensor at the blood lumen outlet to determine the temperature of blood leaving the connector.

In an alternate embodiment of a connector for use with an autoretroperfusion and hypothermia system, the cooling product is at a cooled temperature before entering the coolant inlet.

In a further embodiment of a connector for use with an autoretroperfusion and hypothermia system, the connector comprises a blood lumen inlet for receiving a patient's blood and a coolant inlet for receiving a cooling product, wherein the blood lumen inlet and the coolant inlet are positioned at a first end of the connector; a reservoir for receiving the cooling product from the coolant inlet; a blood lumen outlet and a coolant outlet for receiving the cooling product from the reservoir, wherein the blood lumen out and the coolant outlet are positioned at a second end of the connector; and a blood lumen defined within the reservoir and extending between the blood lumen inlet and the blood lumen outlet.

In an embodiment of a method for using a connector for use with an autoretroperfusion and hypothermia system, the steps include: introducing a patient's blood and a cooling product into a first end of the connector; flowing the blood and cooling product through the connector wherein the cooling product cools the blood; allowing the cooled blood and cooling product to exit a second end of the connector.

In an embodiment of a method for using a connector for use with an autoretroperfusion and hypothermia system, blood flows through the connector solely under the power of the patient's own heart.

In an embodiment of a method for using a connector for use with an autoretroperfusion and hypothermia system, the method further includes the step of cooling the cooling product before the step of introducing the patient's blood and the cooling product at the first end of the connector.

In an embodiment of a method for using a connector for use with an autoretroperfusion and hypothermia system, the method further includes the step of measuring a temperature of the blood at the second end of the connector without contacting the blood.

In an embodiment of a method for using a connector for use with an autoretroperfusion and hypothermia system, the method further includes the step of adjusting the temperature of the cooling product based on the measured temperature of blood.

In an embodiment of a method for using a connector for use with an autoretroperfusion and hypothermia system, the blood exiting the connector at the second end of the connector exits at a pressure less than 50 mmHg.

In an embodiment of a method for using a connector for use with an autoretroperfusion and hypothermia system, the method further includes the steps of: connecting an arterial blood source at the first end of the connector; connecting a catheter at the second end of the connector; and wherein the patient's blood flows from the arterial blood source, through the connector, and into the catheter.

In an embodiment of a method for using a connector for use with an autoretroperfusion and hypothermia system, the method further includes the step of connecting a cooling system at the coolant inlet and the coolant outlet and using the cooling system to cool the cooling product.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a side view of a catheter for placement within an arterial vessel and that may be used to deliver retroperfusion therapy, according to at least one embodiment of the present disclosure;

FIG. 2A shows a side view of the catheter of FIG. 1 in a collapsed position, according to at least one embodiment of the present disclosure;

FIG. 2B shows a side view of the catheter of FIG. 1 in an extended position, according to at least one embodiment of the present disclosure;

FIG. 3 shows a side view of an autoretroperfusion system positioned to deliver retroperfusion therapy to a heart, according to at least one embodiment of the present disclosure;

FIGS. 4A and 4B show perspective views of the distal end of a venous catheter used in the autoretroperfusion system of FIG. 3, according to at least one embodiment of the present disclosure;

FIG. 5 shows the components of an autoretroperfusion system that can be used to deliver retroperfusion therapy to ischemic tissue, according to at least one embodiment of the present disclosure;

FIG. 6 shows a view of the base and diaphragmatic surface of a heart with the distal ends of two components of the autoretroperfusion system of FIG. 5 positioned therein such that the autoretroperfusion system can deliver simultaneous selective autoretroperfusion therapy thereto, according to at least one embodiment of the present disclosure;

FIG. 7 shows a flow chart of a method for delivering autoretroperfusion therapy, according to at least one embodiment of the present disclosure;

FIG. 8A shows a side view of the catheter of FIG. 1 in a collapsed position within an introducer, according to at least one embodiment of the present disclosure;

FIG. 8B, shows a side view of the catheter of FIG. 1 being introduced via an introducer into an arterial vessel, according to at least one embodiment of the present disclosure;

FIGS. 8C and 8D show side views of the introducer of FIG. 8A being removed from an arterial vessel, thereby deploying the projection cannula of the catheter of FIG. 1, according to at least one embodiment of the present disclosure;

FIG. 8E shows a side view of the catheter of FIG. 1 anchored within an arterial vessel through the use of an expandable balloon, according to at least one embodiment of the present disclosure;

FIG. 9 shows a schematic view of the autoretroperfusion system of FIG. 5 as applied to a heart, according to at least one embodiment of the present disclosure;

FIG. 10 shows a schematic view of the autoretroperfusion system of FIG. 5 as applied to a heart, according to at least one embodiment of the present disclosure;

FIG. 11 shows a schematic view of a step of the method of FIG. 7 as the method is applied to a heart, according to at least one embodiment of the present disclosure;

FIG. 12 shows a flow chart of a method for delivering simultaneously selective autoretroperfusion therapy, according to at least one embodiment of the present disclosure;

FIG. 13 shows a schematic view of a step of the method of FIG. 12 as the method is applied to a heart, according to at least one embodiment of the present disclosure;

FIG. 14 shows a schematic view of a step of the method of FIG. 12 as the method is applied to a heart, according to at least one embodiment of the present disclosure;

FIG. 15 shows an exemplary retroperfusion system, according to at least one embodiment of the present disclosure;

FIG. 16 shows a portion of an exemplary retroperfusion system, according to at least one embodiment of the present disclosure; and

FIG. 17 shows a block diagram of components of an exemplary retroperfusion system coupled to a blood supply, according to at least one embodiment of the present disclosure;

FIG. 18 shows a schematic of the retroperfusion system showing the arterial and retroperfusion catheters, according to a study in connection with the present disclosure;

FIG. 19 shows a diagram of steps of an exemplary method of organ perfusion, according to at least one embodiment of the present disclosure;

FIG. 20 shows a block diagram of a regional hypothermia system and kit used in connection with an exemplary device or system of the present disclosure;

FIG. 21 shows an intravenous arterialization catheter, according to an exemplary embodiment of the present disclosure;

FIG. 22 shows a biodegradable intravenous arterialization catheter, according to an exemplary embodiment of the present disclosure;

FIG. 23A shows steps of a method of using an intravenous arterialization catheter, according to an exemplary embodiment of the present disclosure;

FIG. 23B shows an embodiment of a catheter positioned within a vein and connected to a graft in communication with an artery, according to an exemplary embodiment of the present disclosure;

FIG. 23C shows steps of another method of using an intravenous arterialization catheter, according to an exemplary embodiment of the present disclosure;

FIG. 24A shows an intravenous arterialization catheter, according to an exemplary embodiment of the present disclosure;

FIG. 24B shows an embodiment of a catheter positioned subcutaneously and into a vein and connected to a graft in communication with an artery, according to an exemplary embodiment of the present disclosure;

FIG. 25 shows an intravenous arterialization catheter, according to an exemplary embodiment of the present disclosure;

FIGS. 26A and 26B show embodiments of a catheters positioned into a human and animal vein, respectively, according to exemplary embodiments of the present disclosure;

FIG. 27 shows an exemplary embodiment of a mild hypothermia selective auto-retroperfusion (MH-SARP) system, according to at least one exemplary embodiment of the present disclosure;

FIG. 28A shows a distal portion of a catheter, according to at least one exemplary embodiment of the present disclosure;

FIG. 28B shows a component diagram of portions of an exemplary system 100 of the present disclosure, according to at least one exemplary embodiment of the present disclosure;

FIG. 28C shows a diagram of how a MH quick connector could be used with a mammalian body, according to at least one exemplary embodiment of the present disclosure;

FIGS. 29A and 29B show an image of an isolated wedge preparation (FIG. 29A) and regional distribution of mild hypothermia (FIG. 29B).

FIG. 30 shows a chart depicting representative experimental tracing taken from a subendocardial temperature probe.

FIGS. 31A and 31B show charts depicting infarct area (FIG. 31A) and associated CTnI levels over time (FIG. 31B) for the various control, normothermia and hypothermia retroperfusion cohorts.

FIGS. 32A and 32B show charts depicting ST segment changes in response to initial ischemic insult and followed by retroperfusion (FIG. 32A) and the frequency of PVCs observed during reperfusion (FIG. 32B).

FIGS. 33A, 33B, and 33C show charts depicting metabolic indices of cardiac metabolism in response to treatment conditions. Elevations in effluent oxygen during retroperfusion (FIG. 33A) support conversion to anaerobic glycolysis and ischemic metabolism as evidenced by increases in glucose uptake (FIG. 33B) and lactate release (FIG. 33C) across the retroperfused myocardium.

FIG. 34 shows an image of a representative immunohistology for reperfusion injury marker caspase-3. In agreement with supporting data, caspase-3 expression (red) is elevated in control (B) specimens compared to normothermia (C) and hypothermia (D) explanted hearts which approximate healthy viable myocardium (A).

FIGS. 35A and 35B show levels of miR-1 (FIG. 35A) and miR-133a (FIG. 35B), novel biomarkers of reperfusion injury, measured in blood plasma.

FIG. 35C shows myocardial sections obtained from approximately the same regions in control, normothermia, and hypothermia groups, double-stained with Evans blue and TTC, where the infarcted area (white) is clearly demarcated in the control group (left panel) vs. normothermia (central panel) and hypothermia (right panel) groups.

An overview of the features, functions and/or configurations of the components depicted in the various figures will now be presented. It should be appreciated that not all of the features of the components of the figures are necessarily described. Some of these non-discussed features, such as various couplers, etc., as well as discussed features are inherent from the figures themselves. Other non-discussed features may be inherent in component geometry and/or configuration.

DETAILED DESCRIPTION

For the purposes of promoting an understanding of the principles of the present disclosure, reference will now be made to the embodiments illustrated in the drawings, and specific language will be used to describe the same. It will nevertheless be understood that no limitation of the scope of this disclosure is thereby intended.

The embodiments discussed herein include devices, systems, and methods useful for providing selective autoretroperfusion to the venous system. In addition, and with various embodiments of devices and systems of the present disclosure, said devices and/or systems can also be used to achieve a controlled arterialization of the venous system

The devices, systems and methods disclosed herein can be used to safely and selectively arterialize venous vessels in order to decrease the stress thereon and prevent rupture of the same. Accordingly, through the use of the devices, systems and methods disclosed herein, long-term autoretroperfusion of oxygenated blood through the coronary venous system can be achieved, thereby providing a continuous supply of oxygen-rich blood to an ischemic area of a tissue or organ. While the devices, systems and methods disclosed herein are described in connection with a heart, it will be understood that such devices, systems and methods are not limited in their application solely to the heart and the same may be used in connection with any ischemic tissue and/or organ in need of an oxygen-rich blood supply.

Selective auto-retroperfusion (SARP) can be indicated for both chronic and acute applications, and exemplary catheters 10 and/or systems 100 of the present disclosure (and as referenced in further detail herein) can be used in connection therewith. References to “acute” for SARP applications are used generally to indicate the amount of time that an exemplary catheter 10 and/or system 100 of the present disclosure may be in use on a given patient. In at least one embodiment, catheter 10 and/or system 100, or portions thereof, will be sterile and intended for disposal after a single use. In at least one embodiment of a system 100 useful in connection with an acute indication, use of system 100 could be limited to less than 24 hrs.

Now referring to FIG. 1, a side view of a catheter 10 is shown. The catheter 10 is configured to be placed within an arterial vessel and comprises a flexible, elongated tube having a proximal end 12, a distal end 14 and at least one lumen 15 extending between the proximal end 12 and the distal end 14. The dimensions of the catheter 10 may vary depending on the particulars of a specific patient or with respect to the artery to be cannulated. For example and without limitation, where the catheter 10 is used to in a system for autoretroperfusion of the coronary sinus, the catheter 10 may comprise a diameter of about 2.7 millimeters to about 4 millimeters (about 8 Fr to about 12 Fr). Furthermore, the at least one lumen 15 of the catheter 10 comprises a sufficient diameter such that blood can flow therethrough. In addition, the catheter 10 may be comprised of any appropriate material, including without limitation, polyurethane or silicone rubber. Furthermore, the catheter 10 may be coated with heparin or any other suitable anti-coagulant such that the catheter 10 may be placed within a vessel for an extended period of time without inhibiting blood flow due to coagulation.

The distal end 14 of the catheter 10 is configured to allow arterial blood to flow therethrough and into the at least one lumen 15 of the catheter 10. Similarly, the proximal end 12 of the catheter 10 is configured to allow blood within the at least one lumen 15 to flow out of the catheter 10. Accordingly, when the catheter 10 is positioned within an arterial vessel, the oxygenated blood is allowed to flow into the catheter 10 through the distal end 14 of the catheter 10, through the at least one lumen 15, and out of the catheter 10 through the proximal end 12 of the catheter 10. In this manner, placement of the catheter 10 within a vessel does not inhibit the flow of blood through the vessel or significantly affect the pressure of the blood flow within the vessel.

As shown in FIG. 1, the catheter 10 further comprises a projection cannula 16 that extends from the proximal end 12 of the catheter 10 and forms a Y-shaped configuration therewith. The projection cannula 16 comprises a flexible tube of material that is appropriate for insertion within a vessel and placement within an opening in a vessel wall. Furthermore, the projection cannula 16 comprises at least one lumen 18, a proximal end 20, and a distal end 22. The distal end 22 of the projection cannula 16 is coupled with the body of the catheter 10 and configured to allow the lumen 18 of the projection cannula 16 to communicate with at least one of the at least one lumens 15 of the catheter 10. Accordingly, when blood flows through the at least one lumen of the catheter 10, a portion of the blood flow enters the lumen 18 of the projection cannula 16 through the distal end 22 thereof and flows out through the proximal end 20 of the projection cannula 16. In this manner, the catheter 10 is capable of bifurcating the flow of blood through the vessel in which it is inserted and routing some of that blood flow out of the vessel and to another location.

This bifurcation can be exploited to modify the pressure of the blood flowing through the projection cannula 16 and/or through the proximal end 12 of the catheter 10 by manipulating the dimensions of the projection cannula 16 and the body of the catheter 10. For example, and without limitation, if the diameter of the projection cannula 16 is less than the diameter of the at least one lumen 15 of the catheter 10, the majority of the blood will flow through the proximal end 12 of the catheter 10 and the pressure of the remaining blood that flows through the smaller projection cannula 16 will necessarily be reduced. Predictably, the smaller the diameter of the lumen 18 of the projection cannula 16, the greater the pressure drop that can be achieved in the blood flowing through the lumen 18 of the projection cannula 16. Accordingly, with respect to the catheter's 10 application to autoretroperfusion therapies, the projection cannula 16 can be used to re-route blood flow from an artery to a vein while simultaneously achieving the necessary pressure drop in the re-routed blood between the arterial system and unarterialized venous system. Moreover, the catheter 10 is capable of maintaining substantially normal blood flow through the artery in which it is housed as the arterial blood not re-routed through the projection cannula 16 is allowed to flow through the open proximal end 12 of the catheter 10 and back into the artery in the normal antegrade fashion.

Due to the configuration of the projection cannula 16 and the material of which it is comprised, the projection cannula 16 is capable of hingedly moving relative to the body of the catheter 10 between a collapsed position and an extended position. Now referring to FIGS. 2A and 2B, the projection cannula 16 is shown in the collapsed position (FIG. 2A) and in the extended position (FIG. 2B). When the projection cannula 16 is in the collapsed position, the projection cannula 16 is positioned substantially parallel with the body of the catheter 10. Alternatively, when the projection cannula 16 is in the extended position, the projection cannula 16 is positioned such that the projection cannula 16 forms an angle θ with the proximal end 12 of the catheter 10. The value of angle θ may be selected depending on the desired application of the catheter 10. For example, in at least one embodiment, the angle θ may comprise any value ranging between about 15° and about 90°. In another example, the angle θ may comprise about 45° when the projection cannula 16 is in the extended position.

The projection cannula 16 is biased such that, when it is not subject to a downward force, the projection cannula 16 rests in the expanded position. Conversely, when a downward force is applied to the projection cannula 16 by way of an introducer or otherwise, the projection cannula 16 moves into and remains in the collapsed position until the downward force is removed. In this manner, the projection cannula 16 may be introduced into a vessel in the collapsed position through the use of an introducer or shaft and thereafter move into the expanded position when the catheter 10 is properly positioned within the vessel and the introducer or shaft is removed.

Optionally, as shown in FIG. 1, the catheter 10 may further comprise an expandable balloon 58 coupled with an intermediary portion of the external surface of the catheter 10 such that the expandable balloon 58 encases the catheter 10 and the distal end 22 of the projection cannula 18. The expandable balloon 58 may be any expandable balloon 58 that is appropriate for insertion within a vessel and may comprise any material suitable for this function, including without limitation, polyethylene, latex, polyestherurethane, polyurethane, sylastic, silicone rubber, or combinations thereof. In operation, the expandable balloon 58 can be used to anchor the catheter 10 in a desired position within a vessel wall and prevent leakage from the opening in the vessel wall through which the projection cannula 16 traverses.

The expandable balloon 58 is capable of being controlled by a clinician such that it can inflate and/or deflate to the proper size. The sizing of the expandable balloon 58 will differ between patients and applications. The expandable balloon 58 may be in fluid communication with a balloon inflation port 62 through a secondary lumen 60 within the lumen 18 of the projection cannula 16. Alternatively, the expandable balloon 58 may be in fluid communication with the balloon inflation port 62 through a tube or other means that is positioned within the lumen 18 of the projection cannula 16 as shown in FIG. 1. The balloon port 62 may be positioned subcutaneously or otherwise such that a clinician can easily access the balloon port 62 when the catheter 10 is positioned within a vessel. In this manner the balloon port 62 can be accessed by a clinician, subcutaneously, percutaneously or otherwise, and used to inflate or deflate the expandable balloon 58 with no or minimal invasion to the patient.

Now referring to FIG. 3, an autoretroperfusion system 100 is shown positioned to allow arterial blood to irrigate the coronary sinus of a heart 101. With respect to the heart 101, the autoretroperfusion system 100 may be used for treatment of myocardial infarctions by injecting arterial blood into the coronary sinus in synchronism with the patient's heartbeat. Furthermore, the autoretroperfusion system 100 is capable of controlling the pressure of the arterial blood flow as it enters the venous vessel such that when the arterial blood flow is first introduced into the venous system, the pressure of the re-routed arterial blood flow is reduced to protect the thinner venous vessels. In this manner, the venous system is allowed to gradually arterialize. Further, after the selected venous vessel has sufficiently arterialized, the autoretroperfusion system 100 is capable of reducing or ceasing its influence on the pressure of the re-routed arterial blood flow such that the standard arterial blood flow pressure is thereafter allowed to flow into the arterialized venous vessel.

Autoretroperfusion system 100 comprises the catheter 10, a second catheter 150, and a connector 170. The catheter 10 is for placement within an arterial vessel and is configured as previously described in connection with FIGS. 1-2B. The second catheter 150 is configured for placement within the venous system. The connector 170 is configured to form an anastomosis between the catheter 10 and the second catheter 150 and further functions to monitor various data points on the blood flow flowing therethrough. In addition, in at least one embodiment, the connector 170 is capable of controlling the pressure of arterial blood flowing therethrough.

The second catheter 150 is configured for placement within a venous vessel wall 114 and comprises a flexible tube having a proximal end 152, a distal end 154 and at least one lumen 156 extending between the proximal end 152 and the distal end 154. Both the proximal end 152 and the distal end 154 of the second catheter 150 are open and in communication with the at least one lumen 156 of the second catheter 150, thereby allowing blood to flow into the at least one lumen 156 through the proximal end 152 and out of the distal end 154 back into the venous vessel 114. The second catheter 150 may be any catheter known in the art that is capable of intravascular insertion and advancement through the venous system and may comprise any appropriate material, including without limitation, polyurethane or silicone rubber. In at least one embodiment, the second catheter 150 is configured to receive a guidewire 510 (see FIGS. 4A and 4B) through the at least one lumen 156 to facilitate the intravascular delivery of the distal end 154 of the second catheter 150 into the desired location of the venous vessel 114. Furthermore, similar to the catheter 10, the second catheter 150 may be coated with heparin or any other suitable anti-coagulant prior to insertion in order to facilitate the extended placement of the second catheter 150 within the venous vessel 114. Accordingly, the autoretroperfusion system 100 may be used to deliver chronic retroperfusion treatment to an ischemic area of a body.

FIGS. 4A and 4B show side views of the distal end 154 of the second catheter 150 positioned within the venous vessel wall 114. As shown in FIG. 4A, the distal end 154 of the second catheter 150 may further comprise an expandable balloon 158 coupled with the external surface of the second catheter 150. In operation, the expandable balloon 158 can be used to anchor the distal end 154 of the second catheter 150 in the desired location within the venous vessel wall 114. The expandable balloon 158 may be any expandable balloon that is appropriate for insertion within a vessel and can be formed of any material suitable for this function, including without limitation, polyethylene, latex, polyestherurethane, polyurethane, sylastic, silicone rubber, or combinations thereof.

The expandable balloon 158 is capable of being controlled by a clinician such that it can inflate and/or deflate to the proper size. The sizing of the expandable balloon 158 will differ between patients and applications and it is often important to determine the proper sizing of the expandable balloon 158 to ensure the distal end 154 of the second catheter 150 is securely anchored within the desired location of the vessel wall 114. The accurate size of the expandable balloon 158 can be determined through any technique known in the art, including without limitation, by measuring the compliance of the expandable balloon 158 ex vivo or in vivo. In addition, the distal end 154 of the second catheter 150 may further comprise a plurality of electrodes that are capable of accurately measuring the cross-sectional area of the vessel of interest as is known in the art. For example, the plurality of electrodes may comprise a combination of excitation and detection electrodes as described in detail in the currently pending U.S. patent application Ser. No. 11/891,981 entitled System and Method for Measuring Cross-Sectional Areas and Pressure Gradients in Luminal Organs, and filed on Aug. 14, 2007, which is hereby incorporated by reference in its entirety. In at least one embodiment, such electrodes may comprise impedence and conductance electrodes and may be used in connection with ports for the suction of fluid from the vessel and/or the infusion of fluid therein.

The expandable balloon 158 may be in fluid communication with a secondary lumen 160 disposed within the at least one lumen 156 of the second catheter 150. In this example, the secondary lumen 160 is coupled with a balloon port 162 that extends from the proximal end 152 of the second catheter 150 (see FIG. 3). Accordingly, when the autoretroperfusion system 100 is positioned within a patient, the balloon port 162 can be easily accessed by a clinician, subcutaneously, percutaneously or otherwise, and used to inflate or deflate the expandable balloon 158 with no or minimal invasion to the patient.

As shown in FIGS. 4A and 4B, the distal end 154 of the second catheter 150 may further comprise at least one sensor 166 coupled therewith. In at least one embodiment, the at least one sensor 166 is disposed on the distal end 154 of the second catheter 150 distally of the expandable balloon 158; however, it will be understood that the at least one sensor 166 may be disposed in any location on the distal end 154 of the second catheter 150.

The at least one sensor 166 may be used for monitoring purposes and, for example, may be capable of periodically or continuously monitoring the pressure of the blood flow flowing through the at least one lumen 156 of the first catheter 150 or the venous vessel 14 in which the second catheter 150 is inserted. Additionally, one of the at least one sensors 166 may be used to monitor the pH or the concentrations of carbon dioxide, lactate, or cardiac enzymes within the blood. Furthermore, the at least one sensor 166 is capable of wirelessly communicating the information it has gathered to a remote module through the use of telemetry technology, the internet, or other wireless means, such that the information can be easily accessed by a clinician on a real-time basis or otherwise.

Now referring back to FIG. 3, the autoretroperfusion system 100 further comprises a connector 170. The connector 170 comprises any connector or quick connector known in the medical arts that is capable of forming an anastomosis between an artery and a vein such that oxygenated blood from the arterial system can flow into the venous system. For example, the connector 170 may comprise an annular connector that is capable of coupling with the proximal end 20 of the projection cannula 16 of the catheter 10 and with the proximal end 152 of the second catheter 150 such that arterial blood can flow continuously from the at least one lumen 15 of the catheter 10 to the at least one lumen 156 of the second catheter 150. The connector 170 may be formed of any suitable material known in the art including, but not limited to, silicon rubber, poly(tetrafluoroethene), and/or polyurethane.

The connector 170 of the autoretroperfusion system 100 may comprise a pressure/flow regulator unit that is capable of measuring the flow rate of the blood moving therethrough, the pressure of the blood moving therethrough, and/or other data regarding the blood flowing through the anastomosis. The connector 170 may also be capable of transmitting such gathered data to a remote module 180 through a lead placed intravascularly or, in the alternative, through telemetry or another wireless means. The remote module 180 may comprise any device capable of receiving the data collected by the connector 170 and displaying the same. For example, and without limitation, the remote module 180 may comprise any display device known in the art or a computer, a microprocessor, hand-held computing device or other processing means.

Additionally, the connector 170 may further comprise a means for regulating the blood flow through the anastomosis. One of the main challenges of successfully delivering retroperfusion therapies is that the arterial blood pressure must be reduced prior to being introduced into a vein due to the thinner and more fragile anatomy of venous walls. Indeed, subjecting a non-arterialized venous vessel to the high pressures of arterial blood flow typically results in rupture of the venous vessel. Accordingly, with retroperfusion therapies, it is critical to ensure that the pressure of the arterial blood flow is at least initially controlled such that the venous vessel can arterialize prior to being subjected to the unregulated pressure of the arterial blood flow.

In at least one embodiment the connector 170 may comprise an external compression device to facilitate the control of the flow rate of the blood moving through the anastomosis. Alternatively, other means that are known in the art may be employed to regulate the blood flow and pressure of the blood flowing through the anastomosis formed by the connector 170. In at least one embodiment, the means for regulating the blood flow through the anastomosis formed by the connector 170 is capable of regulating the pressure and/or flow velocity of the blood flowing through the anastomosis. For example, the means for regulating blood flow can be adjusted to ensure that about a 50 mg Hg pressure drop occurs in the blood flow between the arterial vessel and the venous vessel.

The connector 170 is capable of not only transmitting data to the remote module 180, but also receiving commands from the remote module 180 and adjusting the means for regulating blood flow pursuant to such commands. Accordingly, when the autoretroperfusion system 100 is positioned within a patient for retroperfusion therapy, a clinician can use the remote module 180 to view the blood flow data collected by the connector 170 and non-invasively adjust the connector 170 to achieve the desired pressure and/or flow through the anastomosis. Such remote control of the connector 170 is particularly useful as a clinician may incrementally decrease the connector's 170 regulation of the blood flow without surgical intervention during the venous arterialization process and/or after the venous vessel arterializes.

Further, where the remote module 180 comprises a computer or other processing means, the remote module 180 is also capable of being programmed to automatically analyze the data received from the connector 170 and, based on the results thereof, suggest how to adjust the means of regulating the blood flow of the connector 170 and/or automatically adjust the means of regulating the blood flow of the connector 170 to achieve the optimal result. For example, and without limitation, when the autoretroperfusion system 100 is implanted into a patient and the anastomosis is first performed, the remote module 180 can automatically adjust the means for regulating the blood flow of the connector 170 based on the initial blood flow data received by the remote module 180. In this manner, the desired pressure drop between the arterial system and the venous system is immediately achieved and the risk of venous rupture is significantly reduced.

Alternatively, where the connector 170 of the autoretroperfusion system 100 does not comprise a means for regulating blood flow, the gradual arterialization of the venous vessel can be achieved through other techniques known in the art. For example, in at least one embodiment, the autoretroperfusion system 100 further comprises a coil designed to at least partially occlude the vein of interest. In this manner, the pressure is allowed to build in front of the portion of the vein at least partially occluded by the coil and the vein gradually arterializes. In this at least one embodiment, the coil may comprise a metallic memory coil (made of nitinol, stainless steel or other acceptable materials that are radioopaque) and is covered with polytetrafluorethylene, polyethylene terephthalate, polyurethane or any other protective covering available in the medical arts.

Additionally, gradual arterialization can be performed by the second catheter 150. In this embodiment of autoretroperfusion system 100, the at least one lumen 156 of the second catheter 150 is designed to provide an optimal stenosis geometry to facilitate the desired pressure drop as the arterial blood flows therethrough and into the venous system. For example, and without limitation, the at least one lumen 156 may further comprise an internal balloon or resorbable stenosis as disclosed in International Patent Application No. PCT/US2006/029223, entitled “Devices and Methods for Controlling Blood Perfusion Pressure Using a Retrograde Cannula,” filed Jul. 28, 2006, which is hereby incorporated by reference herein.

In at least one embodiment, the stenosis comprises an internal expandable balloon (not shown) positioned within the lumen 156 of the second catheter 150. In this at least one embodiment, the internal expandable balloon can be used to provide a pressure drop between the arterial and venous systems as is required to achieve the gradual arterialization of the target vein. The internal expandable balloon and the external expandable balloon 158 of the second catheter 150 may positioned concentrically or, alternatively, the internal expandable balloon and the expandable balloon 158 may be coupled with distinct portions of the second catheter 150.

The internal expandable balloon may comprise any material suitable in the medical arts, including, without limitation, polyethylene, latex, polyestherurethane, polyurethane, sylastic, silicone rubber, or combinations thereof. Further, the internal expandable balloon may be in fluid communication with a tertiary lumen (not shown) disposed within the at least one lumen 156 of the second catheter 150. In this embodiment, the tertiary lumen is also in fluid communication with an internal balloon port that extends from the proximal end 152 of the second catheter 150. Accordingly, the internal balloon port can be easily accessed by a clinician, subcutaneously, percutaneously or otherwise, and the internal balloon port can be used to inflate or deflate the internal expandable balloon with minimal or no discomfort to the patient when the system 100 is in operation. Alternatively, the internal expandable balloon may be in fluid communication with the at least one lumen 156 of the second catheter 150. In this example, the arterial blood flow through the at least one lumen 156 functions to inflate and deflate the internal expandable balloon in conjunction with the systolic and diastolic components of a heart beat.

The internal expandable balloon may be sized to a specific configuration in order to achieve the desired stenosis. In one embodiment, the size of the desired stenosis may be obtained by measuring the pressure at the tip of the distal end 156 of the second catheter 150 with the at least one sensor 166 while the internal expandable balloon is being inflated. Once the desired intermediate pressure is obtained, the internal expandable balloon volume may then be finalized and the vein is thereafter allowed to arterialize at the modified pressure for a defined period of time. At the end of the defined period (typically about 2-3 weeks), the internal expandable balloon may be removed from the at least one lumen 156 of the second catheter 150.

Insertion and/or removal of the internal expandable balloon from the system 100 may be achieved through the internal balloon port and the related tertiary lumen of the second catheter 150. For example, if the internal expandable balloon is no longer necessary to control the pressure on the venous system because the arterialization of the vein is substantially complete, the internal expandable balloon can be deflated through use of internal balloon port and withdrawn from the system 100 through the tertiary lumen and the internal balloon port.

Other embodiments of the system 100 may comprise other suitable means for providing a stenosis within the at least one lumen 156 of the second catheter 150 such that a pressure drop is achieved in blood flowing therethrough. For example, while a stenosis can be imposed by inflation of the internal expandable balloon, it may also be imposed through positioning a resorbable material within the at least one lumen 156 of the second catheter 150. The resorbable stenosis may be comprised of a variety of materials including, for example and without limitation, magnesium alloy and polyols such as mannitol, sorbitol and maltitol. The degradation rate of the resulting resorbable stenosis will be dependent, at least in part, upon on what type of material(s) is selected to make-up the resorbable stenosis and the same may be manipulated to achieve the desired effect.

In addition to the aforementioned components of the autoretroperfusion system 100, the autoretroperfusion system 100 may further include a first graft 185 and a second graft 190 as shown in FIG. 3. In this embodiment, the first graft 185 is coupled with the proximal end 20 of the projection cannula 16 (that extends through the exterior arterial wall 116) and the connector 170. Further, the second graft 190 is coupled with the proximal end 152 of the second catheter 150 (positioned within the venous vessel wall 114) and the connector 170. Accordingly, in this at least one embodiment, the second graft 190 is capable of traversing the venous vessel wall 114 in such a manner that the anastomosis is sealed and no blood flow is allowed to leak from the anastomosed vein 114.

In this manner, the first and second grafts 185, 190 facilitate the formation of an elongated anastomosis between the venous and arterial vessels 114, 116 and thereby relieve any pressure that may be applied to the two vessels 114, 116 due to the anastomosis formed therebetween. For example and without limitation, in at least one embodiment the combined length of the grafts 185, 190 and the connector 170 is about 6 centimeters. However, it will be understood that the grafts 185, 190 may comprise any length(s) so long as the dimensions allow for an anastomosis to form between the applicable vessels and a fully developed blood flow is achieved from the artery to the venous vessel of interest.

Alternatively, the autoretroperfusion system 100 may only comprise the second graft 190 in addition to the catheter 10, the second catheter 150 and the connector 170. In this embodiment, the connector 170 is coupled with the proximal end 20 of the projection cannula 16 and the second graft 190. Furthermore, the second graft 190 is further coupled with the proximal end 152 of the second catheter 150 such that the second graft 190 traverses an opening within the venous vessel wall 114 (see FIG. 5).

The grafts 185, 190 may comprise any biocompatible, non-resorbable material having the necessary strength to support the surrounding tissue and withstand the pressure asserted by the blood flow therethrough. Furthermore, the grafts 185, 190 must exhibit the necessary flexibility to form an anastomosis between the vein and the artery within which the catheter 10 and the second catheter 150 are respectively housed. For example, and without limitation, the grafts 185, 190 may comprise any conventional implant including synthetic and natural prosthesis, grafts, and the like. The grafts 185, 190 may also comprise a variety of suitable materials, including those conventionally used in anastomosis procedures, including, without limitation, natural and synthetic materials such as heterologous tissue, homologous tissue, polymeric materials, Dacron, fluoropolymers, and polyurethanes. For example, and without limitation, the first and second grafts 185, 190 may comprise a material such as GORE-TEX (polytetraflouroethylene). The grafts 185, 190 may be coated with heparin or any other suitable anti-coagulant. Accordingly, the first graft 185 and the second graft 190 may be placed within a vessel or have blood flow therethrough for an extended period of time without inhibiting blood flow due to coagulation.

In at least one embodiment of the autoretroperfusion system 100, the components of the system 100 are available in a package. Here, the package may also contain at least one sterile syringe containing the fluid to be injected into the balloon port 62 to inflate the expandable balloon 58 of the catheter 10 and/or the balloon port 162 to inflate the expandable balloon 158 of the second catheter 150. Furthermore, the package may also contain devices to facilitate delivery of the autoretroperfusion system 100 such as venous and arterial access devices, a delivery catheter, a guidewire and/or mandrel, an introducer to maintain the catheter 10 in the collapsed position during delivery and, in those embodiments where a coil is used to arterialize the vein of interest, a pusher bar as is known in the art.

The guidewire used to facilitate the delivery of the autoretroperfusion system 100 into a vessel by providing support to the components thereof. The guidewire may comprise any guidewire known in the art. Furthermore, the distal end of the guidewire may comprise a plurality of impedance electrodes that are capable of taking measurements of the size the vessel in which the guidewire is inserted through the use of impedance technology. Additionally, in at least one embodiment, the impedance electrodes may be further capable of communicating such measurements to the remote module 180 through telemetry or other wireless means in a manner similar to the at least one sensor 166 of the distal end 154 of the second catheter 150. In at least one embodiment, the distal end of the guidewire may comprise two tetrapolar sets of impedance electrodes disposed on its distal-most tip.

Based on the information gathered by the impedance electrodes, a clinician can obtain accurate measurements of a selective region of a vessel. In this manner, the expandable balloon 158 coupled with the distal end 154 of the second catheter 150 may be properly sized and the amount of fluid or gas needed to inflate the expandable balloon 158 can be determined prior to introducing the second catheter 150 into the vein of interest. For example, a clinician can use the plurality of impedance electrodes on the guidewire to obtain measurements of the size and shape of the sub-branches of the coronary sinus. Details regarding the specifications and use of the impedance electrodes are described in detail in the currently pending U.S. patent application Ser. No. 10/782,149 entitled “System and Method for Measuring Cross-Sectional Areas and Pressure Gradients in Luminal Organs,” and filed on Feb. 19, 2004, which is hereby incorporated by reference herein in its entirety.

Now referring to FIG. 5, components of a simultaneous selective autoretroperfusion system 300 are shown. The simultaneous selective autoretroperfusion system 300 (the “SSA system 300”) are configured identically to the autoretroperfusion system 100 except that the SSA system 300 further comprises a third catheter 350 and a Y connector 320, both configured for placement within the venous vessel wall 114. Specifically, the SSA system 300 comprises the catheter 10, the second catheter 150, the third catheter 350, the connector 170, and the Y connector 320. It will be understood that the SSA system 300 can also further comprise the first graft 185 and/or the second graft 190, and the remote module 180 as described in connection with autoretroperfusion system 100.

The third catheter 350 is configured for placement within the venous vessel wall 114 adjacent to the second catheter 150. The third catheter 350 is configured identically to the second catheter 150 and comprises a flexible tube having a proximal end 352, a distal end 354 and at least one lumen 356 extending between the proximal end 352 and the distal end 354. Both the proximal end 352 and the distal end 354 of the third catheter 350 are open and in communication with the at least one lumen 356 of the third catheter 350, thereby allowing blood to flow into the at least one lumen 356 through the proximal end 352 and out of the distal end 354 back into the venous vessel 114.

The third catheter 350 may be any catheter known in the art that is capable of intravascular insertion and advancement through the venous system. The third catheter 350 may comprise any appropriate material, including without limitation, polyurethane or silicone rubber. In at least one embodiment, the third catheter 350 is configured to receive a guidewire 310 (see FIGS. 5 and 6) through the at least one lumen 356 in order to facilitate the intravascular delivery of the distal end 354 of the third catheter 350 into the desired location of the venous vessel 114. Furthermore, the third catheter 350 is coated with heparin or any other suitable anti-coagulant prior to insertion in order to facilitate the extended placement of the third catheter 350 within the venous vessel 114.

As shown in FIG. 5, the distal end 354 of the third catheter 350 further comprises an expandable balloon 358 coupled with the external surface of the third catheter 350. In operation, the expandable balloon 358 can be used to anchor the distal end 354 of the third catheter 350 in the desired location within the venous vessel wall 114. The expandable balloon 358 may be any expandable balloon that is appropriate for insertion within a vessel and can be formed of any material suitable for this function, including without limitation, polyethylene, latex, polyestherurethane, polyurethane, sylastic, silicone rubber, or combinations thereof.

Similar to the expandable balloon 158 of the second catheter 150, the expandable balloon 358 is capable of being controlled by a clinician such that it can inflate and/or deflate to the proper size. The appropriate size of the expandable balloon 358 can be determined through any technique known in the art, including without limitation, by measuring the compliance of the expandable balloon 358 ex vivo or in vivo. Furthermore, when the guidewire 310 is used to facilitate the delivery of the distal end 354 of the third catheter 350 into the desired location within the venous vessel wall 114, the electrodes on the distal end of the guidewire 310 may be used to accurately measure the cross-sectional area of the venous vessel 114 such that the expandable balloon 358 can be precisely sized prior to insertion into the vein 114.

In this at least one embodiment, the expandable balloon 358 is in fluid communication with a secondary lumen 360 disposed within the at least one lumen 356 of the third catheter 350. In this example, the secondary lumen 360 is coupled with a balloon port 362 that extends from the proximal end 352 of the third catheter 350. Accordingly, when the SSA system 300 is positioned within a patient, the balloon port 362 can be easily accessed by a clinician, subcutaneously, percutaneously or otherwise, and used to inflate or deflate the expandable balloon 358 with no or minimal invasion to the patient.

Similar to the second catheter 150, the distal end 354 of the third catheter 350 may further comprise at least one sensor 366 coupled therewith. The at least one sensor 366 may be configured identically to the at least one sensor 166 of the second catheter 150 and, accordingly, the at least one sensor 366 may be used to monitor the pressure of blood flow through the at least one lumen 356 of the third catheter 350 or the venous vessel 114 or to monitor the pH or the concentrations of carbon dioxide, lactate, or cardiac enzymes within the blood. Furthermore, the at least one sensor 366 is capable of communicating the data it gathers to the remote module 180 through the use of a wireless technology such that a clinician can easily access the gathered information on a real-time basis or otherwise. In at least one embodiment, the at least one sensor 366 is disposed on the distal end 354 of the third catheter 350 distally of the expandable balloon 358; however, it will be understood that the at least one sensor 366 may be disposed in any location on the distal end 354 of the third catheter 350.

The Y connector 320 of the SSA system 300 comprises flexible material and has a proximal end 322, a distal end 324 and at least one lumen 326 extending between the proximal and distal ends 322, 324. The proximal end 322 of the Y connector 322 is open and configured to be securely coupled with the graft 190. The distal end 324 of the Y connector 322 comprises two open ends which extend from the body of the Y connector 322 in a substantially Y-shaped configuration. The two open ends of the distal end 324 of the Y connector 322 thereby divide the at least one lumen 326 into two separate channels and thus the blood flowing through the at least one lumen 326 is yet again bifurcated.

The proximal end 152 of the second catheter 150 is coupled with one of the two open ends of the distal end 324 of the Y connector 322, thereby receiving a portion of the blood flow that flows through the at least one lumen 326 of the Y-connector. Similarly, the proximal end 352 of the third catheter 350 is coupled with the other open end of the distal end 324 of the Y connector 322 and, thus, the third catheter receives a portion of the blood flow that flows through the at least one lumen 326 of the Y-connector. In this manner, the SSA system 300 can be used to simultaneously retroperfuse more than one ischemic area of the body.

In application, the second catheter 150 and the third catheter 350 are positioned adjacent to each other within the venous vessel wall 114 as shown in FIG. 5. Furthermore, the distal ends 154, 354 of the second and third catheters 150, 350, respectively, may be placed within different veins such that the arterial blood is delivered to selective portions of ischemic tissue. For example, as shown in FIG. 6, in at least one embodiment the SSA system 300 can be applied to a heart 314 to provide an arterial blood supply to two separate coronary veins, or sub-branches, simultaneously. In this at least one embodiment, the distal ends 154, 354 of the second and third catheters 150, 350 are both advanced through the coronary sinus 370. As the diameter of the coronary sinus 370 ranges from about 10 to about 20 millimeters, cannulating the coronary sinus 370 with both the second and third catheters 150, 350 does not occlude the normal antegrade flow of the blood therethrough. Upon reaching the veins or sub-branches of interest, the distal ends 154, 354 of the second and third catheters 150, 350 are each independently positioned within the veins of interest. In the example shown in FIG. 6, the second catheter 150 is positioned within the interventricular vein 374 and the distal end 354 of the third catheter 350 is positioned within the middle cardiac vein 376. As with autoretroperfusion system 100, the expandable balloons 158, 358 are inflated through balloon ports 162, 362, respectively (shown in FIG. 5), such that the distal ends 154, 354 of the second and third catheters 150, 350 are securely anchored in the desired location within the veins of interest. In this manner, the SSA system 300 can deliver controlled arterial blood flow to, and thus arterialize, two areas of the heart 314 simultaneously.

In at least one embodiment of the SSA system 300, the components of the system 300 are available in a package. Here, the package may also contain sterile syringes with the fluids to be injected into the balloon ports 162, 362 to inflate the expandable balloons 158, 358, respectively. Furthermore, the package may also contain devices to facilitate delivery of the SSA system 300 such as arterial and venous access devices, a delivery catheter, at least two guidewires (configured as described in connection with the delivery of autoretroperfusion system 100), an introducer to maintain the catheter 10 in the collapsed position during delivery and, in those embodiments where a coil is used to arterialize the vein of interest, a pusher bar as is known in the art.

Now referring to FIG. 7, a flow chart of a method 400 for performing automatic retroperfusion using the system 100 is shown. While the method 400 is described herein in connection with treating a heart through catheterization of the coronary sinus, it will be understood that the method 400 may be used to perform autoretroperfusion on any organ or tissue in need of retroperfusion treatment and/or other areas near the coronary sinus, such as the great cardiac vein, for example.

Method 400, and the embodiments thereof, can be performed under local anesthesia and do not require any arterial sutures. Further, once implanted, the system 100 can deliver chronic treatment to the patient as the system 100 is capable of remaining within a patient's vascular system for an extended period of time. In this manner, the system 100 and method 400 can be used to treat no-option patients and greatly enhance their quality of life.

As shown in FIG. 7, in one approach to the method 400, at step 402 an artery 502 of interest is percutaneously punctured under local anesthesia with a conventional artery access device or as otherwise known in the art. For example and without limitation, in at least one embodiment, an 18 gauge needle is inserted into the femoral or subclavian artery. At step 404, the catheter 10 housed in a collapsed position within an introducer 504 (see FIG. 8A) is inserted into the artery 502 of interest. After the distal end 14 of the catheter 10 is positioned in the desired location within the artery 502, the introducer 504 is proximally withdrawn from the artery 502 as shown in FIG. 8B, leaving the catheter 10 positioned therein.

In at least one embodiment, the projection cannula 16 is configured such that when the introducer 504 is withdrawn in a proximal direction, the proximal end 12 of the catheter 10 is released from the introducer 504 before the proximal end 20 of the projection cannula 16 is released from the introducer 504. In this manner, the proximal end 12 of the catheter 10 is delivered within the interior of the arterial wall 502, while the projection cannula 16 remains housed within the interior of the introducer 504 as shown in FIG. 8C. Furthermore, because the introducer 504 no longer applies downward pressure to the projection cannula 16 relative to the proximal end 12 of the catheter 10, the projection cannula 16 is allowed to shift from the collapsed position to the expanded position and therefore extends in a direction that is not parallel with the artery 502 or the body of the catheter 10. In this manner, as shown in FIGS. 8C and 8D, the proximal end 20 of the projection cannula 16 is directed through the opening formed in the arterial wall 502 by the introducer 504.

Accordingly, when the catheter 10 is positioned within the artery 502, the antegrade blood arterial blood flow is allowed to continue through the artery 502 through the proximal end 12 of the catheter 10, while only a portion of the arterial blood is rerouted through the projection cannula 16 and into the veins 506 of interest. In this manner, the normal blood flow through the artery 502 is not inhibited by operation of the autoretroperfusion system 100. Furthermore, in addition to bifurcating the blood flowing through the artery 502, the projection cannula 16 traversing the arterial wall 502 further functions to anchor the catheter 10 in the desired position within the artery 502.

In the embodiment where the catheter 10 further comprises the expandable balloon 58 (see FIG. 1), step 404 may further comprise inflating the expandable balloon 58 to the desired size by injecting fluid into the balloon port 62. In this manner, the expandable balloon 58 functions to further anchor the catheter 10 in the desired location within the artery 502 and seal the opening in the artery 502 through which the projection cannula 16 projects (see FIG. 8E).

At step 406, a vein 506 of interest is percutaneously punctured under local anesthesia with a conventional venous access device or as otherwise known in the art. For example and without limitation, in at least one embodiment, an 18 gauge needle is inserted into the femoral or subclavian vein. At step 408, a delivery catheter 508 is inserted into and advanced through the vein 506 to catheterize the coronary sinus ostium. A guidewire 510 is then inserted at step 410 into the delivery catheter 510 and advanced into the lumen of the vein 506 through the distal end of the delivery catheter 510. Furthermore, the guidewire 510 is advanced into the region of interest by use of x-ray (i.e. fluoroscopy), direct vision, transesophageal echocardiogram, or other suitable means or visualization techniques.

FIGS. 9 and 10 show schematic views of the method 400 as applied to a heart 500. Specifically, in this at least one embodiment, at steps 402 and 404 the artery 502, which in FIG. 9 comprises the subclavian artery, is punctured and the catheter 10 is inserted and positioned therein. Further, at step 406 the vein 506, which in FIG. 9 comprises the subclavian vein, is punctured and at step 408 the delivery catheter 508 is advanced through the superior vena cava 518 and into the coronary ostium of the coronary sinus 520. As shown in FIG. 10, at step 410, the guidewire 510 is advanced through the coronary sinus 520 and into the vein of interest, which, in this at least one embodiment, comprises the posterior vein 522 of the heart 500.

Now referring back to FIG. 7, the guidewire 510 inserted into the vein 506 at step 410 may further comprise a plurality of impedance electrodes as previously described herein. In this approach, the guidewire 510 may be used at optional step 411 to determine the size of the vessel of interest through use of the plurality of impedance electrodes disposed thereon. In this manner, a clinician can use the measurements generated by the impedance electrodes to select a properly sized expandable balloon 158 for use in connection with the second catheter 150. By using a precisely sized expandable balloon 158 and inflation volume, the clinician can ensure that the distal end 154 of the second catheter 150 is securely anchored within the vessel of interest without imposing an undue force on the venous vessel walls.

After the guidewire 510 has been advanced into the vessel of interest at step 410 and, optionally, the dimensions of the vessel of interest have been measured at step 411, the method 400 advances to step 412. At step 412, the distal end 154 of the second catheter 150 is inserted into the delivery catheter 508 over the guidewire 510. Accordingly, the guidewire 510 is slidably received by the at least one lumen 156 of the second catheter 150. The distal end 154 of the second catheter 150 is then advanced over the guidewire 510 to the region of interest and the expandable balloon 158 of the second catheter 150 is inflated to anchor the distal end 154 within the targeted vessel. FIG. 11 shows a schematic view of the method 400, as applied to the heart 500, after step 412 has been completed. It will be understood that at any point after the distal end 154 of the second catheter 150 is positioned and anchored within the desired location in the targeted vessel, the delivery catheter 508 and the guidewire 510 may be withdrawn from the vein of interest.

After the distal end 154 of the second catheter 150 is secured within the targeted vessel, at step 414 the anastomosis between the vein 506 and the artery 502 is formed. Specifically, in at least one approach, the proximal end 20 of the projection cannula 16 of the catheter 10 is coupled with the proximal end 152 of the second catheter 150 by way of the connector 170. In the at least one embodiment of the system 100 comprising the first graft 185 and the second graft 190, the connector 170 may be coupled with the catheter 10 and the second catheter 150 via the first graft 185 and the second graft 190 to form an elongated anastomosis. Alternatively, in yet another approach, the connector 185 may be coupled with the catheter 10 via the proximal end 20 of the projection cannula 16 and the second catheter 150 via only the second graft 190. It will be understood that any combination of the catheter 10, the second catheter 150 and the first and second grafts 185, 190 may be used in connection with the connector 170 to form the desired anastomosis between the vein 506 and the artery 502.

After the anastomosis is formed and the arterial blood is allowed to flow through the anastomosis and thereby through the connector 170, at step 416 the connector 170 measures the flow rate, pressure and any other desired data of the arterial blood flow. The connector 170 transmits the collected data to the remote module 180 either through intravascularly placed leads or wirelessly, through telemetry or other means. In this manner, a clinician may easily view the blood flow data on the remote module 180 and assess the degree of pressure drop that will be required to preserve and gradually arterialize the vein 506.

At step 418, the pressure of the arterial blood flow through the system 100 is modified to transmit the desired pressure to the venous system. In this step 418 the pressure modification can be achieved through a clinician modifying the means of regulating the blood flow of the connector 170 through remote means or, in at least one embodiment of the system 100, inflating the internal expandable balloon of the second catheter 150 using the internal balloon port in order to partially occlude the flow of arterial blood through the at least one lumen 156 of the second catheter 150. Furthermore, in at least one alternative embodiment of the system 100, a clinician may deliver a resorbable stenosis configured to achieve the necessary pressure drop into the at least one lumen 156 of the second catheter 150 through means known in the art.

Alternatively, as previously described in connection with autoretroperfusion system 100, the remote module 180 may further comprise a computer or other processing means capable of being programmed to automatically analyze the data received from the connector 170 and, based on such data, determine the proper degree of adjustment required in the blood pressure flowing through the anastomosis. In this embodiment, at step 418, the remote module 180 automatically adjusts the means of regulating the blood flow of the connector 170 to achieve the optimal pressure drop. In this manner, the desired pressure drop between the arterial system and the venous system is immediately achieved and the risk of venous rupture is significantly reduced.

In step 420 the method 400 allows the arterial blood having a modified pressure to irrigate the vein 506 for a period of time such that the vein 506 properly arterializes. For example, and without limitation, the patient's venous system may be subjected to the reduced arterial pressure for about fourteen days to allow the vein 506 to adapt to the elevated blood pressure flowing therethrough.

After arterialization of the vein 506 is achieved, at step 422 the patient may optionally undergo a coronary venous bypass graft surgery and the components of the autoretroperfusion system 100 may be removed. However, as previously discussed, even with a properly arterialized vein 506, many patients that require retroperfusion therapy may still not be candidates for a coronary vein bypass graft surgery. In the event that the patient is unable to tolerate such a procedure, after the vein 506 has arterialized at step 420, the method 400 can progress directly to step 424. At step 424, the pressure modification of the arterial blood flowing through the second catheter 150 is ceased. Accordingly, pre-arterialized veins 506 are subjected to the full arterial pressure of the blood flowing through the anastomosis and second catheter 150. In at least one embodiment, a clinician can cease the pressure modification by adjusting the controller 170. Alternatively, in the at least one embodiment where the controller 170 can be automatically adjusted by the remote module 180, the remote module 180 can automatically adjust the controller 170 after the veins 506 have pre-arterialized. Further, where the pressure drop is achieved through the use of an internal expandable balloon positioned within the at least one lumen 156 of the second catheter, the clinician may deflate the internal expandable balloon through the internal balloon port and thereafter withdraw the deflated internal expandable balloon through the tertiary lumen of the second catheter and the internal balloon port. In yet another embodiment where a resorbable stenosis is used to achieve the pressure drop in the arterial blood as it flows through the second catheter 150, the resorbable stenosis can be configured to dissolve after the desired period of time, thereby gradually decreasing the influence the resorbable stenosis has on the pressure of the blood flowing through the at least one lumen 156 of the second catheter over a period of time. Accordingly, the autoretroperfusion system 100 can remain chronically implanted within the patient to deliver oxygen-rich blood to a targeted area of tissue over an extended period of time.

Now referring to FIG. 12, a flow chart of a method 600 for performing simultaneous selective retroperfusion using the SSA system 300 is shown. While the method 600 is described herein in connection with treating a heart 500 through catheterization of the coronary sinus 520, it will be understood that the method 600 may be used to perform autoretroperfusion on any organ or tissue in need of retroperfusion treatment. The reference numerals used to identify the steps of method 600 that are included in the description of method 400 designate like steps between the two methods 400, 600. As such, like steps between the two methods 400, 600 will not be discussed in detail with respect to the method 600 and it will be understood that such description can be obtained through the description of the method 400.

Method 600, and the embodiments thereof, can be performed under local anesthesia and does not require arterial sutures. Further, once implanted, the SSA system 300 can deliver simultaneous chronic treatment to multiple ischemic locations as the system 300 is capable of remaining within a patient's vascular system for an extended period of time and selectively retroperfusion more than one sub-branch of a vein 506.

The method 600 progresses through steps 402 through 410 as previously described in connection with the method 400. After the guidewire 510 is advanced through the coronary sinus 520 and into the first vein of interest, a second guidewire 610 is inserted at step 602 into the delivery catheter 508 adjacent to the guidewire 510, and advanced into the lumen of the vein 506 through the distal end of the delivery catheter 510. The second guidewire 610 is then advanced into a second region of interest by use of x-ray (i.e. fluoroscopy), direct vision, transesophageal echocardiogram, or other suitable means or visualization techniques. The second guidewire 610 is configured similar to the guidewire 510 and is capable of functioning the in the same manner.

FIG. 13 shows a schematic view of the method 600 as applied to a heart 500. Specifically, in this at least one embodiment, FIG. 13 shows the method 600 at step 602 wherein the guidewire 510 is inserted a first vein of interest, which comprises the posterior vein 522 of the heart 500, and the second guidewire 610 is inserted into a second vein of interest, which comprises the interventricular vein 622 of the heart 500.

Now referring back to FIG. 12, the guidewire 610 inserted into the second vein of interest in step 602 may further comprise a plurality of impedance electrodes as previously described with respect to the guidewire 510. In this embodiment, the guidewire 610 may be used at optional step 603 to determine the size of the second vessel of interest through use of the plurality of impedance electrodes disposed thereon. In this manner, a clinician can use the measurements generated by the impedance electrodes to select a properly sized expandable balloon 358 for use in connection with the third catheter 350. By using a precisely sized expandable balloon 358 and inflation volume, a clinician can ensure that the distal end 354 of the third catheter 350 is securely anchored within the second vessel of interest without imposing an undue force on the venous vessel walls.

After the guidewire 610 has been advanced into the second vessel of interest at step 602 and, optionally, the dimensions of the second vessel of interest have been measured at step 603, the method 600 advances to step 412 wherein the second catheter 150 is inserted over the guidewire 510 as described in connection with method 400. At step 604, the distal end 354 of the third catheter 350 is inserted into the delivery catheter 508 over the second guidewire 610. Accordingly, the second guidewire 610 is slidably received by the at least one lumen 356 of the third catheter 350. The distal end 354 of the third catheter 350 is then advanced over the second guidewire 610 to the second region of interest and the expandable balloon 358 of the third catheter 350 is inflated to anchor the distal end 354 within the targeted vessel. FIG. 14 shows a schematic view of the method 600 at step 604 as applied to the heart 500. It will be understood that at any point after the distal ends 154, 354 of the second and third catheters 150, 350 are positioned and anchored in the desired locations within the targeted vessels, the delivery catheter 508 and the guidewires 510, 610 may be withdrawn from the vein 506.

After both the distal end 154 of the second catheter 150 and the distal end 354 of the third catheter 350 are secured within the targeted vessels, the method 600 proceeds to step 414 where the anastomosis is formed between the vein 506 and the artery 502 as described in connection with method 400. Thereafter, the method 600 advances through steps 416 through 424 as described in connection with the method 400. Furthermore, at step 418, it will be recognized that a clinician can independently adjust the pressure drop through the second and third catheters 150, 350 in the event that an internal expandable balloon is used in either or both catheters 150, 350 or resorbable stenosis are employed within the at least one lumens 156, 356 of the second and third catheters 150, 350. Alternatively, in the at least one embodiment where the controller 170 comprises a means for regulating the blood flow through the anastomosis, the pressure of the arterial blood flowing through both the second and third catheters 150, 350 may be substantially the same.

As described herein, the method 600 may be used to simultaneously and immediately treat two different ischemic areas of a tissue through the use of one minimally to non-invasive procedure. Furthermore, the method 600 can provide no-option patients with a viable treatment option that is not associated with contraindications for congestive heart failure, diabetes, or drug treatment.

An additional embodiment of a perfusion system 100 of the present disclosure is shown in FIG. 15. As shown in FIG. 15, system 100 comprises a first catheter 1000 having a distal end 1004, a proximal end 1002, and defining a lumen 1006 therethrough, wherein at least a portion of first catheter 1000 is configured for insertion into a body of a patient, such as into a patient's heart or a patient's vein, for example. First catheter 1000, after insertion into a patient's vein or heart, for example, is capable of providing arterial blood (which is relatively rich in oxygen and other nutrients) thereto by way of transfer of arterial blood from, for example, a patient's artery, as described below, into a proximal catheter opening 1008, through lumen 1006, and out of distal catheter opening 1010. In such a fashion, for example, a system 100 can be referred to as an autoretroperfusion system 100, noting that no outside pumps are necessary (as the patient's own heart serves as the pump), and due to the retrograde nature of the perfusion with respect to such a use. Exemplary uses, as provided in detail herein, are to provide arterial blood, using system 100, to a patient's femoral vein, internal jugular vein, subclavian vein, and/or brachial cephalic vein. In an exemplary embodiment, first catheter 1000 may be tapered toward distal end 1004 to facilitate insertion into a patient.

In at least one embodiment of system 100, and as shown in FIGS. 15 and 16, system 100 comprises a coupler 1012 having an outlet port 1013 and one or more additional ports to facilitate connection outside of the patient's body. For example, and as shown in FIGS. 15 and 16, coupler 1012 comprises an inflation port 1014, whereby fluid and/or gas introduced into inflation port 1014 can be used to inflate an expandable balloon 1016 positioned along first catheter 1000 at or near the distal end 1004 of first catheter 1000. As shown in the figures, and in at least one embodiment, an inflation tube 1018 may be coupled to inflation port 1014 at a distal end 1020 of inflation tube 1018, whereby inflation tube 1018 may also have an optional flow regulator 1022 positioned relative thereto to regulate the flow and/or pressure of fluid and/or gas in and out of a lumen 1024 of inflation tube 1018 to inflate and deflate expandable balloon 1016. Inflation tube 1018 may further comprise a proximal connector 1026 configured to receive fluid and/or gas from a fluid/gas source (not shown), whereby proximal connector 1026 can be positioned at or near a proximal end 1028 of inflation tube 1018, for example. Inflation of expandable balloon 1016, for example, can be used to anchor first catheter 1000 to a desired position within a luminal organ of a patient.

An exemplary coupler 1012 of the present disclosure further comprises an arterial blood port 1030 configured to receive arterial/oxygenated blood from, for example, an arterial blood tube 1032 coupled thereto at or near a distal end 1034 of arterial blood tube 1032. As shown in FIGS. 15 and 16, a blood flow regulator 1036 may be positioned relative to arterial blood tube 1032 and operate to regulate the flow and/or pressure of arterial/oxygenated blood flow therethrough. In at least one embodiment, blood flow regulator 1036 comprises a rotatable dial capable of rotation to apply and/or remove pressure to/from arterial blood tube 1032 to regulate the flow and/or pressure of blood through a lumen 1038 of arterial blood tube 1032 and/or to adjust pressure therein based upon identified blood pressure measurements. Such a blood flow regulator 1036, for example, can be used to control blood pressure to limit injury to the patient's luminal organs (such as the patient's venous system and/or myocardium) and/or to minimize potential edema with respect to the same luminal organs. Arterial blood tube 1032 may further comprise a proximal connector 1040 configured to receive arterial/oxygenated blood from a blood supply, whereby proximal connector can be positioned at or near a proximal end 1040 of arterial blood tube 1032, for example. A coupler catheter 1042, as shown in the component block diagram of system 100 shown in FIG. 17, may be used to couple arterial blood tube 1032 to a blood supply 1044, which, as described herein, could be a patient's own artery using the patient's heart as a pump, or could be an external supply that provides blood to arterial blood tube 1032, which may then be used in connection with an apparatus to remove blood from the patient as well.

Furthermore, and in at least one embodiment, an exemplary coupler 1012 of the present disclosure further comprises a medicament port 1046 configured to receive a medicament, saline, and/or the like, so that the same can enter the patient by way of first catheter 1000. Medicament port 1046, as shown in FIGS. 15 and 16, may receive a medicament tube 1048 defining a lumen 1050 therethrough, whereby a distal end 1052 of medicament tube 1048 can couple to medicament port 1046 so that a medicament, saline, and/or the like can be introduced from a medicament source (not shown) coupled to medicament tube 1052 at or near a proximal end 1054 of medicament tube 1048. Exemplary medicaments may include, but are not limited to, fibrinolitic drugs, cardiotonic drugs, antirrhytmic drugs, scavengers, cells or angiogenic growth factors, for example, through the coronary vein or another luminal organ. In at least one embodiment, and as shown in FIGS. 15 and 16, medicament tube 1048 can be branched, whereby a second proximal end 1056 of medicament tube 1048 can receive a medicament and control the flow of medicament therethrough, for example, by way of a medicament regulator 1058 positioned relative to medicament tube 1048, for example. Furthermore, one or more of proximal end 1054 and second proximal end 1056 may be configured to receive a wire therein, such as, for example, a 0.035″ guidewire and/or a 0.014″ pressure wire. As generally referenced herein, any blood, air, fluid, medicament, wire, etc. that enters coupler 1012 by way of inflation port 1014, arterial blood port 1030, and/or medicament port 1046 and eventually enters a lumen of first catheter 1000 will enter one or more of said ports of coupler 1012 and exit outlet port 1013 at the time of entry into first catheter 1000.

FIG. 17, as referenced above, is a block diagram of various components of an exemplary system 100 of the present disclosure. As shown therein, an exemplary embodiment of a system 100 of the present disclosure comprises a first catheter 1000, a coupler 1012, an arterial blood tube 1032 with a blood flow regulator 1036, and a coupler catheter 1042 configured to for connection to a blood supply 1044, wherein the blood supply may or may not be considered as part of a formal system 100. In addition, an exemplary system 100 may comprise an inflation tube 1018 with a flow regulator 1022, whereby an end of inflation tube 1018 is configured for connection to a gas/liquid source 1060. Various embodiments of systems 100 of the present disclosure may have more or less components than shown in FIG. 17, and exemplary embodiments of systems 100 of the present disclosure may be configured to engage various embodiments of catheters 10 as referenced herein.

In use, for example, first catheter 1000 of system 100 may be positioned within a luminal organ of a patient within the patient's venous system. Inflation of expandable balloon 1016 to secure first catheter 1000 can not only provide oxygenated arterial blood to the patient's venous system, but can also continue to allow coronary venous return to continue due to the selective autoretroperfusion nature of an exemplary embodiment of system 100 and use thereof and due to the redundancy of the patient's venous system. In the event that an increased pressure, edema, or other undesired condition may occur at or near the site of inflated expandable balloon 1016, a user of system 100 could, if desired, temporarily deflate expandable balloon 1016 to allow the increased pressure and or edema to alleviate itself. For example, system 100 could be used for a relatively long period of time (an hour, by way of example), and expandable balloon 1016 could be deflated for a relatively short period of time (seconds, for example), to alleviate a high pressure or edema occurrence, and then expandable balloon 1016 could be re-inflated to again secure first catheter 1000 at a desired location within the patient.

The type of patients for whom the device will be utilized in the acute application may fall into various categories, including, but not limited to, S-T segment Elevated Myocardial Infarction (STEMI) patients, cardiogenic shock patients, and high risk Percutaneous Coronary Intervention (PCI) patients (such as those undergoing PCI of the left main coronary artery). STEMI is the traditional “emergent” patient who presents with classic heart attack symptoms, and when diagnosed in a hospital emergency room for example, the patient would traditionally be immediately moved to a Cath Lab to receive PCI to open an occluded coronary artery and restore blood flow to the myocardium. These patients are hemodynamically unstable and need support for the left ventricle.

In such a use, for example, an exemplary system 100 of the present disclosure could be used to, for example:

(i) provide cardiac support to a patient who does not have immediate access to the Cath Lab and PCI. These patients may present in rural or community hospitals that do not have Cath Labs. They will need some type of temporary support while being transferred to an appropriate facility. These patients might also present at a hospital with a Cath Lab, but the Cath Lab is either understaffed to treat the patient, or does not have an available room to treat. In these cases, the system 100 of the present disclosure operates as a bridge to provide support until definitive treatment (primary PCI) is available; and/or

(ii) provide cardiac support before, during, and after primary PCI. Many patients enter the Cath Lab in an unstable condition, and the insertion of balloons and stents adds to hemodynamic instability. An exemplary system 100 can provide cardiac support and improve hemodynamics such that the physician can operate in a more stable/controlled environment. It is also believed that by reperfusing ischemic myocardium before/during/and after primary PCI, one may reduce the amount of myocardium that is damaged by the ischemic event. This is clinically referred to as a “reduction in infarct size.” Initial animal studies (as referenced in further detail herein) have suggested that the use of SARP in support of STEMI patients could cause a reduction in infarct size, which would have a significant impact on the outcomes for the patient in both the near and long term. Reduction in infarct size would slow the progression of any subsequent heart failure and reduce long term hospitalization and costs for this group of patients.

Cardiogenic shock is marked by a significant lowering of blood pressure and cardiac output that if not reversed, will ultimately lead to multisystem organ failure and death. Cardiogenic shock patients have a mortality exceeding 60%. In many cases, cardiogenic shock patients are too unstable to undergo surgery or PCI. Pharmacologics are used to increase pressure and cardiac output. Intra Aortic Balloon Pumps (IABP) and other LVAD type products are also employed to improve hemodynamics in an attempt to reverse the downward cycle of cardiogenic shock patients Exemplary embodiments of systems 100 of the present disclosure could be used in much the same fashion.

High Risk PCI is typically defined as patients who have disease of the left main coronary artery, are diabetic, have multivessel disease, are above 75 years of age, have a prior history of MI, have renal insufficiency, etc. These are very sick patients, who are considered at high risk of adverse events before, during, and after undergoing PCI. Mortality rates and Major Adverse Cardiac Event (MACE) rates are much higher in this patient population. IABP's are commonly used in this patient population.

In this population, systems 100 of the present disclosure may be used to provide cardiac support for a high risk PCI patient who is, at the time of the procedure, found to be hemodynamically unstable. It is evident to the operator that cardiac support is and will be needed during the procedure, and an exemplary system 100 of the present disclosure would be deployed from the outset. The patient's hemodynamics improve and the operator feels more comfortable working in the coronary system. IABP use is common in these patients.

Systems 100 of the present disclosure may also be used in this high risk population when it is anticipated that cardiac support may be needed during the procedure. In this case, an exemplary system 100 is deployed prior to the case, in order to provide support when and if it is needed. The patient is hemodynamically stable at the outset, and remains so throughout. IABP's are currently used in this fashion. This is commonly referred to as prophylactic use of cardiac support.

Acute Applications: In this setting, exemplary systems 100 of the present disclosure will be used for cardiac support and to protect myocardium for a period of time that will generally be less than 24 hours. The clinical condition that precipitated the need for SARP will have typically been resolved in that 24 hour period, and the system 100 would be removed. However, use of systems 100 of the present disclosure are not limited to a 24 hour period, as in some cases, IABPs and other short term cardiac support devices are left in for periods exceeding 24 hours. Typically, the longest period of time that a short term device might be left in place is 4-6 days, at which point the clinician would begin to consider longer term implanted Left Ventricular Assist Devices (LVADs), which can support a patient for an extended period of time (weeks), and are often used as a bridge to heart transplant.

Clinical conditions that would require the acute application of an exemplary system 100 of the present disclosure include, but are not limited to:

(i) Emergent treatment of STEMI and/or other Acute Myocardial Infarction (AMI) patients;

(ii) Cardiogenic shock;

(iii) High Risk PCI;

(iv) Failed or aborted PCI where severe hemodynamic instability presents after initiation of the procedure. These patients are often transferred to immediate cardiac surgery, and require cardiac support while waiting for the surgical intervention; and/or

(v) Weaning from a cardiopulmonary bypass machine in cardiac surgery. Some cardiac surgery patients have difficulty returning to normal cardiac condition when the cardiopulmonary bypass machine is turned off and the heart is restarted after successful revascularization in cardiac surgery. Exemplary systems 100 of the present disclosure could be used to support the heart until normal cardiac parameters return. Insertion could occur in the surgical suite, and the device would be left in place while the patient was transferred to a Cardiac Critical Care Unit (CCU).

These exemplary clinical conditions cover the majority of potential applications for an acute embodiment of a system 100 of the present disclosure. Currently, more than 95% of all IABP and other short term support devices are used for these applications.

In such applications, the goal of using an exemplary system 100 of the present disclosure is to deliver arterial (oxygenated) blood to the myocardium, in a retrograde manner using the venous system, in order to create hemodynamic stability for the patient and to protect and preserve myocardial tissue until the clinical event resolves or primary intervention (PCI or CABG) and revascularization can occur.

Chronic Applications: In this setting it is intended that an exemplary embodiment of a system 100 of the present disclosure be implanted for 2 weeks or longer, for example, noting that ultimate implantation may be somewhat shorter in duration. Initial animal studies suggest that within 2 weeks, arterialization of the venous system is achieved, such that the venous system can become the conduit for a constant flow of arterial blood at arterial pressure.

A clinical condition where the chronic application of a system 100 would be utilized is often referred to as “no option” patients, that is, patients for which there are no options available through which their clinical condition can be resolved. More specifically, these are patients with diffuse coronary artery disease (CAD) or refractory angina, where PCI and/or Coronary Artery Bypass Graft Surgery (CABG) is not an option. Patients that are diabetic, or have other co-morbidities, and are not candidates for interventions, would be candidates for a chronic application of a system 100 of the present disclosure.

As previously referenced herein, the chronic application will generally require 10-14 days of retroperfusion in order to allow arterialization of the venous system. In certain instances, retroperfusion could be required for a longer period (such as 2-3 weeks, for example), or a lesser period, such as less than 10 days, for example. These patients, dependent upon their complete clinical situation, may be hospitalized for that period, or they may reside outside of the hospital. When residing outside of the hospital, the device utilized may be a catheter 10 embodiment with a branched implantable portion, such as shown in FIG. 1, for example. The catheter 10, including method of pressure regulation, would be implanted in the patient.

For those chronic patients, who must remain in the hospital for one of the aforementioned time periods, an acute embodiment of a system 100, for example, may be applicable. In such an embodiment, for example, system 100 may be percutaneously inserted and utilized during that time frame. Once arterialization occurs, a more permanent conduit may be constructed percutaneously or surgically to provide the permanent arterial blood source.

When using an exemplary system 100 of the present disclosure, standard guide catheters can be used by the clinician to locate the coronary sinus and/or the great cardiac vein, for example. An 0.035″ guidewire can be inserted to further establish access to the coronary sinus or the great cardiac vein. An exemplary system 100 can then be inserted over the 0.035″ guidewire and advanced to the coronary sinus or the great cardiac vein, for example, via one of the ports as referenced herein.

The distal end 1004 of the first catheter 1000 is intended to be located at the left main vein. The operator may advance the tip (distal end 1014) of first catheter 1000 to other vein sites dependent on clinical need. A balloon 1016, which in at least one embodiment may be located approximately 2 cm back from the distal end 1004, would then be inflated to secure the position of first catheter 1000 within the coronary sinus or the great cardiac vein, for example, allowing for the distal end 1004 of first catheter 1000 to locate at the left main vein. The inflated balloon 1016 will also work to ensure that arterial blood will flow in the retrograde fashion.

Once the distal balloon 1016 is inflated, the 0.035″ guidewire can be exchanged for an 0.014″ pressure measurement wire, which will be used to measure the pressure at the distal end 1004 of first catheter 1000, to ensure that the portions of system 100 are not over pressurizing the vein, and to tell the operator how much pressure change will be required from the external pressure regulator. The proximal end of the pressure wire will be connected to its appropriate monitor.

When the catheter is located in the coronary sinus or the great cardiac vein, for example, the operator can now make the external (outside the body) connection to the arterial blood supply 1044. This is typically, but not limited to, the femoral or radial arteries. The physician will have previously inserted a standard procedural sheath into the arterial source in order to gain access to the source. This arterial sheath can also be used to provide access for catheters, guidewires, balloons, stents, or other devices that might be utilized while treating the patient. That arterial sheath will have a connector which can connect to the arterial supply cannula (with regulator) on the acute device (an embodiment of system 100). Once the connection is established and flow commences, the pressure wire will indicate the distal pressure measurement and the regulator can be adjusted to the proper setting (not to exceed 60 mmhg, for example). Monitoring of the distal pressure will be on-going throughout the period of time that the device is in-vivo. The regulator allows the operator to provide the correct distal pressures and to adjust those pressures, dependent on changes in the patient's pressure.

With the pressure set and monitored, the patient is now receiving oxygenated blood to the myocardium in a retrograde fashion thru the coronary venous system. Such an operation (namely to retrogradly provide oxygenated blood) can be used to save a significant amount of ischemic tissue at the level of the border zone. In at least one embodiment, such a system 100 is used to perfuse the left anterior descending vein to supply oxygenated blood to the LAD artery occluded territory. Depending upon patient need and circumstance, the acute device (an embodiment of system 100) will be removed typically within the first 24 hours of insertion. The physician will make that determination. The insertion site will be closed per hospital protocol.

Validation of Methodology

As referenced in detail herein, coronary artery disease (CAD) is the number one cause of morbidity and mortality in the U.S. and worldwide. Even today, with percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass grafting (CABG), optimal and timely treatment is still not available for all patients. Bridge therapies to complement existing gold standards of reperfusion therapy would be of significant value to a large number of patients.

Because the coronary venous system rarely develops atherosclerosis, the use of the venous system for delivery of oxygenated blood has been well explored. Synchronized retrograde perfusion (SRP) and pressure-controlled intermittent coronary sinus occlusion (PICSO) are two retroperfusion methods for acute treatment of myocardial ischemia through the coronary venous system. PICSO and SRP have been used in conjunction with a balloon-tipped catheter positioned just beyond the orifice of the coronary sinus connected to a pneumatic pump, and either passively redirect coronary sinus blood (PICSO) or actively pump arterial blood during diastole (SRP) to the ischemic myocardium. These techniques have been shown to decrease ischemic changes, infarct size, myocardial hemorrhage, and no-reflow phenomenon, and improve left ventricular (LV) function when coronary blood flow is reinstituted after an acute occlusion. Wide application of these techniques, however, has been limited by concerns over their safety and complexity, and in particular, the need for repeated occlusion of the coronary sinus with a balloon. High pressure (SRP and PICSO) and flow (SRP) can cause damage to the coronary sinus with thrombosis and chronic myocardial edema.

We have validated in animal studies both the acute and chronic application of the methodologies referenced herein. In a recent acute study, we showed that preservation of the contractile function of the ischemic myocardium can be accomplished with selective autoretroperfusion (SARP) without the use of an external pump during acute LAD artery ligation. The hypothesis that SARP can preserve myocardial function at regulated pressures without hemorrhage of vessels or damage of myocytes was verified. In connection with this animal work, a bolus of Heparin was given before instrumentation and was then supplemented as needed to keep an activated clotting time (ACT) over 200 seconds. The right femoral artery was cannulated with a 7Fr catheter and connected to a pressure transducer (TSD104A—Biopac Systems, Inc) for monitoring of arterial pressure. Before the sternotomy, the right carotid artery was cannulated with a 10Fr polyethylene catheter through a ventrolateral incision on the neck to reach the brachiocephalic artery to supply the LAD vein during retroperfusion. The catheter had a roller clamp that was used to control the arterial pressure transmitted to the LAD vein. The right jugular vein was cannulated with an 8Fr catheter for administration of drugs and fluids. Lidocaine hydrochloride was infused at a rate of 60 μg/kg/min before opening the chest and during the rest of the procedure. Magnesium sulfate (10 mg/min IV) along with lidocain was also used to treat extrasystole in the case of the control group. A vasopressor (Levophed®, Norepinephrine Bitartrate Injection, Minneapolis, Minn., 2-6 μg/min IV) was used during the procedure, and was adjusted accordingly to maintain a constant arterial blood pressure (70.0±8.9 mmHg, mean) in both the experimental and the control groups. Finally, heparin and nitroglycerine were diluted in 60 mL of 0.9% sodium chloride and infused using a syringe pump at a rate of 1 ml/min. The chest was opened through a midsternal thoracotomy, and an incision was made in the pericardium with the creation of a sling to support the heart with pericardial stay sutures.

A pair of piezoelectric ultrasonic crystals (2 mm in diameter on 34 gauge copper wire—Sonometrics Corporation) were implanted through small stab incisions in the anterior wall of the LV (area at risk) distal to the planned site (below first diagonal branch in the SARP group, and second diagonal branch in the control group) of LAD artery ligation, for assessment of regional myocardial function through measurement of midwall segment length changes. An additional pair of crystals was also implanted in the anterior wall of the LV within the normal perfusion bed (control area) of the proximal portion of the LAD artery.

FIG. 18 shows a schematic of the retroperfusion system showing the arterial and retroperfusion catheters. Each pair of crystals were positioned in the midmyocardium (about 7 mm from the epicardium) approximately 10-15 mm apart and oriented parallel to the minor axis of the heart. The acoustical signal of the crystals was verified by an oscilloscope.

In the SARP group (ligation+retroperfusion) the LAD artery was dissected free from the surrounding tissue distal to the first diagonal branch for subsequent ligation. A 2.5 mm flow probe was placed around the LAD artery and connected to a flow meter (T403—Transonic Systems, Inc). The LAD vein was also dissected close to the junction with the great cardiac vein, and the proximal portion ligated with 2-0 silk suture in order to prevent runoff to the coronary sinus. The LAD vein was then cannulated below the ligation with a 10Fr cannula that was attached to the brachiocephalic catheter through one of two four-way stopcocks. A flow probe was placed between the stopcocks for measurement of coronary venous flow. Venous pressure was recorded through the pressure monitoring line from the retroperfusion cannula (as shown in FIG. 18). Retroperfusion was initiated immediately after ligation of the LAD artery and was maintained for a period of 3 hours. Arterial blood samples were taken at baseline and at the end of the first, second and third hours of ligation+retroperfusion for monitoring of pH, hematocrit, electrolytes, activated clotting time, and cardiac troponin I.

Coronary venous SARP may be an effective method of protecting the myocardium during acute ischemia before definitive treatment is established as referenced herein regarding various catheter 10 and system 100 embodiments of the present disclosure. SARP may not only offer protection to the ischemic myocardium through retrograde perfusion of oxygenated blood but may also serve as a route for administration of thrombolytics, antiarrhythmics, and cell and gene therapy to the jeopardized myocardium before PTCA or CABG can be implemented in patients eligible for these procedures.

In addition to the foregoing, various devices and systems of the present disclosure can be used to perform methods for retroperfusion of various bodily organs to treat many different types of conditions. As referenced above, providing blood from one bodily vessel to another bodily vessel can be performed using devices and systems of the present disclosure, but in accordance with the following, said devices and systems can also be used to perform the following novel methods and procedures.

As generally referenced above, the concept of using veins to deliver oxygenated nutrient-filled blood (arterial blood) is predicated on the fact that despite any extent of the coronary arterial disease, the corresponding venous counterpart is atherosclerosis-free. An additional fact is that the upper body arterial system has much less predilection for atherosclerosis than the lower body. As such, the present disclosure identifies that the upper body can generally serve as the source of arterial blood to the venous systems of organs with arterial disease, and that devices and systems of the present disclosure can also be used in that regard.

An additional characteristic of the venous system necessary to facilitate SARP (as referenced herein) is the existence of a redundancy of the venous system (namely multiple veins per artery as well as interconnections between venous vessels) to ensure proper venous drainage when portion of the system is used for SARP.

In view of the foregoing, a number of embodiments for retroperfusion of various organs or bodily regions that identify arterial blood donor and organ (venous system) are identified with the present disclosure, including, but not limited to, the following:

(i). Peripheral vessels. Embodiments of devices and systems of the present disclosure can be used to provide oxygenated blood from the femoral artery, the internal femoral artery, or the iliac artery, for example, to the distal saphenous vein or to deep muscle veins for arterialization in diabetic patients (a diffuse disease) to treat, for example a leg pre-amputation or a necrotic or gangrenous foot ulcer. This venous system has valves (typically larger than 1-1.5 mm in diameter) which can be overcome (inverted) through catheterization (namely the insertion of guidewire and SARP catheter, with guidewire dimensions down to 0.35 mm for 0.014″ standard guidewire) to facilitate said peripheral vessel treatment.

(ii). Kidney-Renal Vein. Embodiments of devices and systems of the present disclosure can also be used to facilitate arterialization of the renal vein, which can be partial (polar vein) or total (left or right main veins) by way of the femoral or iliac arteries (if disease free), or from the axillary, brachial, or subclavian arteries of the upper body, if desired. Said procedure could be performed to, for example, treat acute or chronic renal ischemia due to diffuse atherosclerosis, severe intima hyperplasia, and to treat the kidney in connection with various collagen-vascular diseases.

(iii). Intestine (Bowel). A number of arterial sources, such as the femoral, iliac, axiallary, brachial, subclavian, or epigastric arteries, can be used with devices and systems of the present disclosure to facilitate regional arterialization following vein anastomosis (at the vein arch) to treat mesenteric arterial ischemia. In at least one embodiment, said arterialization is performed to treat an acute embolic or thrombotic mesenteric artery occlusion in patients with a severe bowel ischemia.

(iv). Spine. The first of the two main divisions of the spinal system, namely the intracranial veins, includes the cortical veins, the dural sinuses, the cavernous sinuses, and the ophthalmic veins. The second main division, namely the vertebral venous system (VVS), includes the vertebral venous plexuses which course along the entire length of the spine. The intracranial veins richly anastomose with the VVS in the suboccipital region, and caudally, the cerebrospinal venous system (CSVS) freely communicates with the sacral and pelvic veins and the prostatic venous plexus. The CSVS constitutes a unique, large-capacity, valve-less venous network in which flow is bidirectional. The CSVS plays important roles in the regulation of intracranial pressure with changes in posture, and in venous outflow from the brain. In addition, the CSVS provides a direct vascular route for the spread of a tumor, an infection, or an emboli among its different components in either direction. Various embodiments of devices and systems of the present disclosure can be used to provide oxygenated blood from the external carotid artery, the brachial artery, or the axiallary artery, directly to the jugular vein to treat any number of potential spinal injuries or conditions, including spinal cord ischemia.

(v). Penis. Various embodiments of devices and systems of the present disclosure can also be used to provide arterial blood from the epigastric artery to the penile dorsal vein to the cavernous system of the penis to treat erectile dysfunction.

The foregoing examples of organ-specific perfusion protocols are not intended to be exhaustive, but merely exemplary of various novel uses of perfusion devices and systems of the present disclosure. Accordingly, the present disclosure includes various methods for treating organ-related diseases, various methods of providing arterial (oxygenated) blood to veins at or near various organs, and various methods of potentially arterializing veins at or near various bodily organs using devices and systems of the present disclosure.

For example, and as shown in FIG. 19, an exemplary method of organ perfusion of the present disclosure is provided. Method 1900, in at least one embodiment, comprises the steps of positioning at least a portion of a device into a patient's artery (an exemplary artery positioning step 1902), positioning at least a portion of the same or a different device into a patient's vein at or near a target organ (an exemplary vein positioning step 1904), and facilitating operation of the positioned portions to allow blood to flow from the artery to the vein to treat a condition or disease of the target organ (an exemplary operation step 1906).

By way of example, an exemplary artery positioning step 1902 could be performed by positioning at least part of a first catheter 10 having a cannula 16 within an artery of a patient, the first catheter 10 configured to permit arterial blood to flow therethrough and further configured to permit a portion of the arterial blood to flow through the cannula 16, and an exemplary vein positioning step 1904 could be performed by positioning at least part of a second catheter 150 within a vein of the patient at or near a target organ, the second catheter 150 configured to receive some or all of the portion of the arterial blood. In such an embodiment, which may be referred to as a chronic treatment using catheter 10 and catheter 150, an exemplary operation step 1906 involves connecting the cannula 16 of the first catheter 10 to a portion of the second catheter 150 so that some or all of the portion of the arterial blood flowing through the cannula 16 is provided into the vein to treat a condition or disease of the target organ.

Further, and by way of another example, an exemplary artery positioning step 1902 could be performed by positioning at least a portion of an arterial tube 1032 of a perfusion system 100 within an artery of a patient, the arterial tube 1032 configured to permit arterial blood to flow therethrough, and an exemplary vein positioning step 1904 could be performed by positioning at least a portion of a first catheter 1000 of the perfusion system 100 into a vein of the patient at or near a target organ, the first catheter 1000 configured to receive some or all of the arterial blood from the arterial tube 1032. In such an embodiment, which may be referred to as an acute treatment using system 100 of the present disclosure, an exemplary operation step 1906 involves operating a first flow regulator 1036 of the perfusion system 100 so that some or all of the arterial blood flowing through the arterial tube 1032 is provided into the vein to treat a condition or disease of the target organ.

In addition to the foregoing, and in various embodiments of devices (such as catheters 10 and/or cannulas 16), systems 100, and/or SSA systems 300, for example, of the present disclosure, such catheters 10, cannulas 16, and/or systems 100 may optionally comprise a regional hypothermia system 4000 configured in accordance with the following. Various regional hypothermia systems 4000 of the present disclosure, as shown in component block diagram of FIG. 20 and as referenced in further detail herein, are configured for use to cool (reduce the temperature of) blood and/or other fluids within the body for targeted delivery to a location within the body. Such cooling can be from, for example, at or about 0.5° C. to as much as 10° C. cooler, for example, than the native temperature of blood within the mammalian body. In some embodiments, localized blood cooling of greater than 10° C. may be desired and accomplished using one or more regional hypothermia systems 4000 of the present disclosure.

In various embodiments, regional hypothermia systems 4000 are configured for use within a mammalian body even at tissues that are relatively difficult to reach due to, for example, potential occlusion of one or more coronary and/or cerebral arteries. Such regional hypothermia systems 4000 of the present disclosure may be useful in connection with the reduction of perfusion injuries by cooling the region of risk, whether it be at, near, or in the heart and/or brain, may be critical to reduce reperfusion injury and to decrease infarct size, for example, prior to opening an artery in the heart or brain. Retroperfusion, as referenced generally herein, provides an ideal mechanism to deliver blood at a target location, and the use of a regional hypothermia system 4000 of the present disclosure in connection with one or more catheters 10, cannulas 16, systems 100, and/or SSA systems 300 of the present disclosure can effectively deliver blood at a desired/targeted temperature by way of delivery through open veins, for example, to the region at risk, such as a heart or brain. In general, such catheters 10, cannulas 16, systems 100, and/or SSA systems 300, in connection with the use of one or more regional hypothermia systems 4000 of the present disclosure, can allow perfusion/retroperfusion of oxygenated blood, control blood perfusion pressure within a vessel, condition a blood vessel to operate under higher blood pressure (such as arterialization of a vein), increase flow of oxygenated blood to ischemic myocardium, and/or decrease the acute ischemic area during a myocardial infarct event, all at a relatively colder temperature than would otherwise be allowed without the use of a regional hypothermia system.

In at least one embodiment of a regional hypothermia system 4000 of the present disclosure, and as shown in FIG. 20, regional hypothermia system 4000 comprises a heat exchanger 4002 coupled to one or more components of catheters 10, cannulas 16, systems 100, and/or SSA systems 300 of the present disclosure, such as, for example, catheter 10, cannula 16, second catheter 150, connector 170, first graft 185, second graft 190, Y connector 320, third catheter 350, first catheter 1000, arterial blood tube 1032, coupler catheter 1042, and/or other components referenced herein. Heat exchanger 4002, in various embodiments, is configured to reduce the temperature of blood passing through one or more components of catheters 10, cannulas 16, systems 100, and/or SSA systems 300, so that the blood that is ultimately delivered to the targeted area of interest, such as being at, near, or in the heart and/or brain, is at a lower temperature than normal (or without the use of a regional hypothermia system 4000). For example, and in at least one embodiment, regional hypothermia system 4000 is used to reduce the temperature of blood delivered at, near, or in the heart and/or brain by or about 3° C. to 4° C. via the general blood circuit created using various catheters 10, cannulas 16, systems 100, and/or SSA systems 300.

Heat exchanger 4002, as referenced herein, can utilize one or more cooling products 4004, such as perfluorocarbon, liquid carbon dioxide, helium, another cooled gas, and/or another refrigerant or refrigeration mechanism known in the art, that facilitates the cooling of blood, and ultimately tissues at or near the cooled blood, through components of catheters 10, cannulas 16, systems 100, and/or SSA systems 300 of the present disclosure. Furthermore, one or more temperature sensors 4006 can be coupled to various components of catheters 10, cannulas 16, systems 100, and/or SSA systems 300 of the present disclosure, catheter 10, cannula 16, second catheter 150, connector 170, first graft 185, second graft 190, Y connector 320, third catheter 350, first catheter 1000, arterial blood tube 1032, coupler catheter 1042, and/or other components referenced herein, so that blood and/or tissue temperature(s) (including temperatures at, near, or in the heart and/or brain, depending on the type of catheters 10, cannulas 16, systems 100, and/or SSA systems 300 used) can be detected by temperature sensors 4006 and transmitted (via wire or wirelessly) to a remote module 270 and/or another data acquisition and processing system/mechanism so that a user of regional hypothermia system 4000 can regulate localized temperature (at, near, or in the heart or brain, for example), as desired. A generic device 4008 is shown in FIG. 20 as being operably coupled to an exemplary regional hypothermia system 4000 of the present disclosure, whereby generic device 4008 may comprise one or more catheters 10, cannulas 16, systems 100, SSA systems 300, other devices and/or systems of the present disclosure, and/or individual components thereof. An exemplary kit 4010 of the present disclosure, as shown in the figures, comprises an exemplary regional hypothermia system 4000 operably coupled to an exemplary generic device 4008 of the present disclosure.

Further, and in various embodiments, heat exchanger 4004 can be at the level of an arterial-venous connector, a double-lumen catheter, and/or another component of one or more catheters 10, cannulas 16, systems 100, and/or SSA systems 300 of the present disclosure. For the heart, this can be particularly important for patients with a door-to-balloon time of greater than two hours, for patients with ST segment elevation myocardial infarction (STEMI) that are at high risk for reperfusion injury, and/or patients with hemodynamics instability. There are several advantages to using a regional hypothermia system 400 of the present disclosure, including but not limited to rapid percutaneous insertion and rapid cooling of the myocardial area before opening the culprit artery to avoid the cascade of inflammatory reactions responsible for reperfusion injury.

As referenced generally above, various regional hypothermia systems 4000 of the present disclosure are configured and operable to introduce mild hypothermia to reduce cardiac infarct size and general severity of the same. Such systems 4000, in connection with various catheters 10, cannulas 16, systems 100, and/or SSA systems 300 of the present disclosure, can treat chronic and acute heart failure, as needed, and generally reduce the severity of an injury and/or reduce inflammation as referenced herein, by way of regionally reducing blood temperature.

The disclosure of the present application also relates to a potential goal of translating the efficacy of a currently invasive open surgery that requires destruction of vein valves and induces edema due to the transmission of arterial blood pressure to the veins to a mini-surgical/percutaneous procedure that is much less invasive, takes less time and does not require removal of valves and damps the pressure to the veins to reduce the edema.

In lower extremities with total or near complete obstruction of arterial blood flow, the perfusion of the limb in a retrograde manner through the venous system with arterial blood using various devices of the present disclosure will provide adequate oxygen and nutrient supply/demand matching to salvage limb function. Accordingly, the present disclosure includes methods of using venous circulation as an alternative method of limb salvage to deliver arterial blood in a retrograde manner to the ischemic extremity through a novel retroperfusion devices that will transform a lengthy surgical procedure into a simpler surgical/percutaneous hybrid procedure. In the absence of substantial forward native arterial pressure in the capillaries, arterial blood fed into the venous system at higher pressure than the native venous pressure will stimulate the development of significant collateral network between the native arteries and newly arterialized veins to supply nutritive flow and adequate oxygenation to the ischemic tissue and thus salvage the limb (to avoid amputation).

An exemplary catheter for facilitating intravenous arterialization of the present disclosure is shown in FIG. 21. Catheter 3100, as shown in FIG. 21, is configured as a hybrid endovascular catheter and comprises an elongated body 3102 having a proximal end 3104 and a distal end 3106. A balloon 3108 (which may be any number of inflatable members used in the catheter arts), in at least one embodiment, is positioned along elongated body 3102 and may be located closer to distal end 3106 than proximal end 3104. Balloon 3108, in various embodiments, may either be expandable (inflatable) as desired, using a gas and/or a liquid for example, or may be inflated automatically using a gas and/or a liquid, the latter referred to herein as being “autoexpandable.”

As shown in FIG. 21, exemplary catheters 3100 of the present disclosure have a plurality of apertures 3110 defined through elongated body 3102 at or near distal end 3106. Apertures 3110 are configured to allow fluid, such as oxygenated arterial blood, to flow from within a catheter lumen 3112 defined along a longitudinal length of elongated body 3102 out of apertures 3110 and into a luminal organ of interest, such as to an ischemic venous blood vessel. Apertures 3110, in certain other embodiments, may extend either an entire, substantial, or partial length of catheter 3110, and the number, concentration, and/or size of apertures 3110 can vary, as can the dimensions (such as internal diameter or cross-sectional area of catheter 3100) so to control the pressure by way of a pressure drop so that oxygenated arterial blood flowing through catheter 3100 and out of apertures 3110 is at a pressure or pressure range that the venous system can handle. Accordingly, various catheter 3100 features (such as length and diameter) can be tested to ensure proper pressure/flow relationships for the types of resistances that will be experienced in-vivo.

To facilitate proper guidance and positioning within a luminal organ of interest, various catheter 3100 embodiments of the present disclosure are configured to receive a guidewire 3114 therein (such as within lumen 3112 of catheter 3100), whereby guidewire 3114 could be positioned within catheter 3100 between a proximal opening 3116 (also referred to as a “lateral entrance”) and a distal opening 3118 of catheter 3100 as shown in FIG. 21, for example.

In addition, and in at least one embodiment of a catheter 3100 of the present disclosure, the proximal end 3104 of catheter 3100 is configured to attach to a graft 3120 (which may also be referred to herein as a “prosthesis”), with said connection by way of an optional connector 3122 (also referred to herein as a “quick connector”) in some embodiments. In embodiments using one or more connectors 3122, proximal end 3104 of catheter 3100 may be configured with a “female” end or using a connector 3122 with a male or female end, and graft 3120 may be configured with a “male” end or using a connector 3122 with a male or female end. In other embodiments, opposing gender connections may appear on said components. As referenced herein, a general system 3150, as identified in FIG. 21, may comprise an exemplary catheter 3100 of the present disclosure and one or more additional elements, such as, for example, an exemplary graft 312, and exemplary guidewire 3114, and/or an exemplary dilator 3402, as shown in FIG. 24B and referenced in further detail herein.

Graft 3120, as shown in FIG. 21, can be used to effectively anastomose an artery of interest to a vein of interest. For example, and as shown in FIG. 23B, a proximal end 3124 of graft 3120 can be positioned within an artery 3220 (such as a femoral artery, as shown in FIG. 23B), and a distal end 3126 of graft 3120 can be positioned within a vein 3222 (such as a saphenous vein, also shown in FIG. 23B) so that oxygenated blood from artery 3220 can flow through a lumen 3128 of graft 3120 and into catheter 3100 coupled thereto, either directly or via the use of a connector 3122. Desired dimensions of graft 3120 would be such that the risk of lumen 3128 closing off (via thrombosis) would be reduced or eliminated. As shown in FIG. 3B, graft 3120 would be positioned within artery 3220 at a location proximal to an area of artery 3220 having diffuse disease (such as atherosclerotic plaques 3224 as shown in the figure), so that the user placing graft 3120 has a level of confidence that sufficient oxygenated arterial blood flow will exist at that location of artery 3220. If properly placed and connected, blood can flow from artery 3220, through graft 3120, into lumen 3112 of catheter 3100, and out of apertures 3110 so to introduce oxygenated blood to the peripheral/collateral veins 3206 at or near the distal end 3106 of catheter 3100 within vein 3222.

In various embodiments of catheters 3100 of the present disclosure, shown in FIG. 21 or otherwise and/or as referenced herein, catheters 3100 may comprise one or more biologically compatible materials, such as polyurethane and/or other synthetic polymers. Grafts 3120 and/or catheters 3100 of the present disclosure may comprise the same or different materials, such as polytetrafluoroethylene (“PTFE”), polyethylene terephthalate (such as Dacron®), and/or other synthetic polymers. In addition, at least one embodiment of a catheter 3100 of the present disclosure is at least partially coated with an anticoagulant and/or an antithrombotic material, such as heparin, for example. An exemplary catheter 3100 and an exemplary graft 3120 of the present disclosure may couple to one another by way of their inherent coupling characteristics and/or using one or more connectors 3122 for anastomosis of graft 3120.

The use of graft 3120 with catheter 3100, in at least one embodiment, allows for a controlled flow of oxygenated blood from an artery into a venous area of interest. Arterialization of a vein, as generally referenced herein, should preferably occur in a controlled or gradual fashion, as a rapid increase in blood flow and pressure to a vein can cause significant swelling, localized blood accumulation, and potential venous rupture. Graft 3120, in various embodiments, can be sutured to the artery and/or vein so to prevent unintended or undesired migration so to stabilize the same. Furthermore, the dimensions of graft 3120 (length, inner diameter or cross-sectional area, etc.) can be varied so to provide an initial controlled measure (flow or pressure) of blood therethrough upon implantation. By controlling the dimensions of graft 3120 and/or catheter 3100, as referenced above, side effects such as edema can be controlled/minimized by reducing the pressure of blood flowing into the vein or veins of interest. Implantation of graft 3120, as referenced in further detail herein, can be performed percutaneously.

An additional catheter 3100 embodiment of the present disclosure is shown in FIG. 2. As shown in FIG. 22, catheter 3100 is configured to fit within an external shaft 3200, with external shaft 3200 being split at its proximal end 3202. Catheter 3100, in such an embodiment, also defines a plurality of apertures 3110 within elongated body 3102 so that fluid can flow through a lumen 3112 of elongated body 3102 and out of apertures 3110.

Exemplary catheters 3100 of the present disclosure, such as shown in FIG. 22, are partially or completely biodegradable and/or bioabsorbable. Various polymers, such as poly(lactic-co-glycolic acid) (“PLGA”), may be used within various catheter 3100 components, such as nodes 3204 shown in FIG. 22. Nodes 3204, as shown therein, would be located on the external wall of catheter 3100 (such as on elongated body 3102) for segmental occlusion at different levels of a luminal organ, such as the saphein vein. Exemplary nodes 3204 can resorb at different times, such as in one or more days, weeks, or months, and differing resorption rates can allow oxygenated blood to be introduced into other areas of the vein proximal to the initial introduction over time to facilitate gradual arterialization of the vein proximal to the initial introduction location. External shaft 3200, in various embodiments, is used/configured to cover apertures 3110, so that if it is desired to arterialize different locations within the vein, external shaft 3200 can be retracted so that additional apertures 3110 proximal to the originally exposed aperture(s) 3100 are exposed to irrigate oxygenated blood to the additional targeted vein area(s). External shaft 3200, in various embodiments, is used/configured to cover nodes 3204, whereby retraction of external shaft 3200 to expose nodes 3204 to blood flow would start/facilitate the process of resorption of nodes 3204.

An exemplary biodegradable and/or bioabsorbable catheter 3100, such as shown in FIG. 22, may have additional features such as those shown in FIG. 21 or as otherwise shown or described herein, such as, for example, a connector 3122.

Exemplary catheters 3100 of the present disclosure may be used in accordance with the following methods, as depicted in step format in FIG. 23A with mammalian body placement shown in FIG. 23B. In an exemplary method 3300 of the present disclosure, a small incision is made at the level of the peripheral artery source, such as the iliac, femoral, or popliteal artery (an exemplary arterial incision step 3302), and the proximal end 3124 of graft 3120 is positioned into the artery and the distal end 3126 of graft 3120 is positioned into the vein of interest, such as the saphenous vein, to anastomose the same (an exemplary graft anastomosis step 3304). Method 3300, in at least one embodiment, further comprises one or more of the steps of puncturing the vein of interest (such as the saphenous vein, for example) (an exemplary venous puncture step 3306), introducing at least part of a guidewire 3114 into the vein through the puncture aperture (an exemplary guidewire insertion step 3308), and the distal advancement (progression) of guidewire 3114 to a location at or near the portion of the vein of interest (such as, for example, the malleolus saphenous vein segment), while avoiding any venous valves along the way if possible (an exemplary guidewire advancement step 3310). Various methods 3300 of the present disclosure further comprise the steps of advancing (progressing) catheter 3100 over guidewire 3114 so that the distal end 3106 of guidewire 3100 is located within the vein at the region of interest (an exemplary catheter advancement step 3312), and connecting catheter 3100 (at, for example, the proximal end 3104 of catheter 3100) to the graft 3120 (at, for example, the distal end 3126 of graft 3120), either directly or using connector 3122, releasing the oxygenated arterial blood and allowing it to flow from the artery into lumen 3112 of catheter 3100 and out of apertures 3110 (an exemplary catheter-graft connection step 3314). Such a mini-surgical procedure, namely the performance of catheter-graft step 3314, will create a graft anastomosis with an artery, such as the femoral artery. This would complete the procedure to allow arterial oxygenated blood to flow from the artery to the vein via graft 3120 and catheter 3100 to various extremities, including the lower extremities. Steps 3310 and/or 3312, or other method 3300 steps of the present disclosure, may be performed using fluoroscopy, intravascular ultrasound (“IVUS”), a surface ultrasound, or other scanning methods so that the user of guidewire 3114 and/or catheter 3100 is aware of the locations of portions of said devices within the patient's vasculature. To avoid or reduce retrograde flow and/or to secure a portion of catheter 3100 within the vein of interest, an exemplary method 3300 of the present disclosure may further comprise the step of inflating balloon 3108 (by way of manually or automatically operating an inflation source operably coupled to balloon 3108) (an exemplary balloon inflation step 3316). Balloon 3108, which in at least one embodiment may be positioned approximately 1-2 cm from the distal end 3106 of catheter 3100, will be inflated to ensure selective retroperfusion of the region of interest (minimize edema) and to prevent antegrade flow of the blood once retroperfusion is established. Steps of methods 3300, as referenced above, may be performed in a different order than described above. For example, step 3304 may be performed after steps 3310 and 3312.

Over time, such as after two to four weeks for example after use of catheter 3100 within the patient, the venous vessels in the area at or distal to the distal end 3106 of catheter 3100 will arterialize, and over a period of approximately four to six weeks, the native arterial system will form collaterals with the newly arterialized venous vessels to revascularize the limb, such as the leg or portions thereof, such as the foot.

After arterialization has been achieved, catheter 3100 can be removed from the patient (an exemplary catheter removal step 3318). However, and prior to catheter 3100 removal, catheter removal step 3318 may further comprise the additional step of connecting the vein to the artery so to provide oxygenated blood to the distal arterialized venous area. Such a step may also include the step of occluding the vein by way of a tying and/or clipping the proximal portion of the vein. In general, removal of catheter 3100 would discontinue the supply of oxygenated blood to the venous region of interest, and connecting the artery to the vein would allow oxygenated blood to continue to flow through the vein. The tying and/or clipping of the vein proximal to the region of interest, using a tie and/or a cutting tool, for example, would eliminate undesired retrograde blood flow through the vein.

The above-referenced exemplary methods 3300, or other methods whereby some of all of an exemplary catheter 3100 of the present disclosure is positioned within a patient's vasculature, would allow the patient to resume or pursue certain mobility, such as walking and sitting if catheter 3100 is positioned within the patient's leg. In such embodiments, catheter 3100 may comprise malleable and non-collapsible biologically-compatible material(s) so to improve overall comfort. However, certain patient's either may not wish to have the majority or all of catheter 3100 positioned within their vasculature, or the treating physician/interventionalist may determine that using catheter 3100 in a different fashion, or a different catheter 3100 embodiment, may be preferred.

Accordingly, at least one additional method 3300 of the present disclosure is depicted in step format in FIG. 23C and described as follows. In at least one additional method 3300 of the present disclosure, method 3300 comprises the steps of implanting catheter 3300 within the patient through a subcutaneous tunnel 3400 parallel or substantially parallel to the length of the vein of interest (such as the saphenous vein), reaching the desired area of interest (such as the malleolus saphein vein segment) (an exemplary catheter implantation step 3350), and making an incision in the skin and isolating the distal end 3106 of catheter 3100 at the level of the malleolus saphein vein segment, for example (an exemplary skin incision step 3352). Step 3350 may be performed via skin puncture as well, using an optional guidewire 3114 and/or an optional dilator 3402, as shown in FIG. 24B if desired. Dilator 3402, in at least one embodiment, comprises an elongated body having a cross-section larger than a cross-section of catheter 3100, so that when dilator 3402 is advanced subcutaneously, catheter 3100 can be positioned within the subcutaneous tunnel created using dilator 3402. In at least another embodiment, and as shown in FIG. 24B, dilator comprises a dilator lumen 3404 defined therethrough along a longitudinal length of dilator 3402, terminating at or near one end with a distal dilator aperture 3406, whereby a guidewire 3114 can be positioned within dilator lumen 3404, and/or whereby device 3100 can be positioned within dilator lumen 3404.

In view of the same, catheter implantation step 3350 may be performed in various manners. For example, catheter implantation step 3350 can be performed by creating a subcutaneous tunnel using dilator 3402, and advancing at least a portion of catheter 3100 within the subcutaneous tunnel. In another embodiment, catheter implantation step 3350 may be performed by introducing and subcutaneously advancing guidewire 3114 into the mammalian patient and advancing at least a portion of catheter 3100 over guidewire 3114. In yet an additional embodiment, catheter implantation step 3350 can be performed by introducing and subcutaneously advancing a guidewire into the mammalian patient, advancing a dilator over the guidewire to create a subcutaneous tunnel, and advancing at least a portion of the catheter within the dilator. In another embodiment, catheter implantation step 3350 can be performed by introducing and subcutaneously advancing a dilator having a dilator lumen defined therein and a guidewire positioned within the guidewire lumen into the mammalian patient to create a subcutaneous tunnel, removing the dilator, and advancing at least a portion of the catheter within over the guidewire. In yet another embodiment, catheter implantation step 3350 can be performed by introducing and subcutaneously advancing a dilator having a dilator lumen defined therein and a guidewire positioned within the guidewire lumen into the mammalian patient to create a subcutaneous tunnel, removing the dilator, and advancing at least a portion of the catheter within over the guidewire.

Exemplary methods 3300 may further comprise the steps of puncturing the vein of interest (such as the saphenous vein) via traditional venous puncture or incision so to form a venous entrance 3408 (an exemplary venous puncture step 3306), and introducing the distal end 3106 of catheter 3100 into the vein of interest (such as the distal malleolus saphenous vein segment) (an exemplary catheter introduction step 3354). Various methods 3300 further comprise the steps of implanting an exemplary graft 3120 (such as by performing arterial incision step 3302) so that the proximal end 3124 of graft 3120 is positioned into the artery and the distal end 3126 of graft 3120 is available to be connected to catheter 3100 at, for example, the proximal end 3104 of catheter 3100, and connecting catheter 3100 (at, for example, the proximal end 3104 of catheter 3100) to the graft 3120 (at, for example, the distal end 3126 of graft 3120), either directly or using connector 3122, releasing the oxygenated arterial blood and allowing it to flow from the artery into lumen 3112 of catheter 3100 and out of apertures 3110 (an exemplary catheter-graft connection step 3314).

Over time, such as after two to four weeks for example, the venous vessels in the area at or distal to the distal end 3106 of catheter 3100 will become fully arterialized, and over a period of approximately four to six weeks, the native arterial system will form collaterals with the newly arterialized venous vessels to revascularize the limb, such as the leg. After arterialization has been achieved, catheter 3100, or remaining non-biodegradable portions thereof, can be removed from the patient (an exemplary catheter removal step 3318). If the entire catheter 3100 is biodegradable or bioresorbable, catheter removal step 3318 may not be required.

The term “collaterals”, as referenced herein, refers generally to the phenomenon that occurs during and after initial arterialization. Arteries and veins tend to run generally parallel to one another, with the veins forming a general drainage system that allows blood to flow back to the heart. By performing one or more methods 3300 as referenced herein, oxygenated blood flows to a vein, for which the increased blood pressure and increased overall blood nutrients facilitates arterializations. Arteries generally do not collateralize with veins, as veins generally have nothing to offer with respect to oxygenated blood or other blood nutrients. Arties having oxygen-deficient or nutrient-deficient blood flowing therethrough will want to connect with arteries having oxygen and/or nutrient rich blood flowing therethrough, but that process is generally limited naturally as arteries would need to be adjacent to one another to facilitate the collateralization process. As arteries and veins overlap one another, various methods 3300 of the present disclosure effectively turn portions of veins into arteries, and the newly-formed arteries can then collateralize with other adjacent arteries and potentially adjacent veins.

Various additional methods 3300 of the present disclosure may further comprise the step of moving catheter 3100 to another location within the vein of interest, or moving catheter 3100 to another vein of interest, so to facilitate arterialization of a second region within the patient's venous vasculature (an exemplary second region arterialization step 3375, such as shown in FIGS. 23A and 23C). For example, catheter-graft connection step 3314, as referenced above, may be performed at a first location, and, after a desired amount of time has elapsed, catheter 3100 can be moved to a second location within the patient's body, allowing for additional localized arterialization to take place via step 3375.

FIG. 24A shows selected components of an exemplary catheter 3100 of the present disclosure useful in connection with method 3300 as depicted in FIG. 23C and referenced above. As shown in FIG. 24A, exemplary catheter 3100 comprises an elongated body 3102, an autoexpandable balloon 3108 and a plurality of apertures 3110 at or near distal end 3106 of elongated body 3102, and a quick connector 3122 at proximal end 3104 of elongated body to connect graft 3120 to elongated body 3102 of catheter 3100.

FIG. 24B shows placement of an exemplary catheter 3100 of the present disclosure in connection with one or more above-referenced methods 3300 whereby catheter 3100 is positioned subcutaneously through a subcutaneous tunnel 3400. As shown therein, the distal end 3106 of catheter 3100 is positioned through a venous entrance 3408 so that arterial (oxygenated) blood can flow through graft 3120, through lumen 3112 of catheter 3100, and out of apertures 3110 into vein 3222 so to arterialize peripheral/collateral veins 3206.

FIG. 25 shows an exemplary catheter 3100 of the present disclosure with certain identified components. As shown therein, catheter 3100 comprises an elongated body 3102 having a proximal end 3104 and a distal end 3106, a balloon 3108 positioned at or near distal end 3106, and a graft 3120 coupled to catheter 3100 at or near proximal end 3104 of catheter 3100.

FIGS. 26A and 26B show embodiments of catheters 3100 of the present disclosure positioned within a veins 3222 of a mammalian circulatory system. As shown therein (human leg in FIG. 26A, animal leg in FIG. 26B), catheter 3100 is positioned within the great saphenous vein (vein 3222), distal to the femoral vein 3600, while an anastomosis 3602 is present between graft 3120 and the femoral artery 3220. Balloon 3108 is shown in its inflated stated, potentially to anchor catheter 3100 within vein 3222 and to prevent retrograde flow of arterial blood through the great saphenous vein 3222 proximal to balloon 3108.

In addition, the use of a graft 3120 and a catheter 3100 of the present disclosure can not only control pressure and flow of blood therethrough to a vein of interest, catheter 3100 can be used in a way to preserve (not destroy) any valves present in the vein where catheter 3100 is implanted. For example, advancement of a guidewire 3114 through lumen 3112 of catheter 3100 and out of distal opening 3118, as shown in FIG. 21, can facilitate advancement of catheter 3100 within the vein of interest, allowing any valves passed by catheter 3100 to resume operation upon withdrawal or bioabsorption of catheter 3100.

In addition to the foregoing, catheter 3100 and/or graft 3120 can be implanted percutaneously, which may be a preferred implantation method for high risk or otherwise compromised patient conditions. For example, graft 3120 can be inserted percutaneously by puncture of the targeted arterial site (identified using echodoppler, angiography, or another scanning method), and catheter 3100 can be inserted percutaneously into the vein (such as the saphein vein, identified using echodoppler, angiography, or another scanning method). Furthermore, connecting catheter 3100 and graft 3120 using a quick connector 3122 percutaneously can also facilitate the movement of catheter 3100 to a second location within the patient or removal out of the patient altogether.

As generally referenced above, exemplary methods 3300 of the present disclosure, and potentially other uses of exemplary catheters 3100 of the present disclosure, have a number of advantages over current invasive surgical procedures. For example, certain traditional surgical procedures not only take several hours to perform, but also are invasive open surgeries where most, if not all, branches off of the vein of interest are ligated, and certain other surgeries actually remove the vein of interest itself, reverse it, and reconnect it, creating additional potential complications. Uses of catheters 3100 of the present disclosure are far less invasive, do not require complicated open surgical procedures, and can be used to treat inoperable lower limbs via gradual and selective retroperfusion/revascularization. Furthermore, and as referenced above, destruction of venous valves is avoided using catheters 3100 of the present disclosure, while certain surgical procedures either intentionally or intentionally destroy or reduce the functionality of said valves.

In addition to the foregoing, various methods 3300 of the present disclosure may be used to direct blood to and arterialize other areas of the mammalian body, not just the peripheral venous system of a patient's leg or foot. For example, other areas of a patient, such as the patient's hands, arms, torso, and other areas, may be targeted as locations to receive arterialized blood using one or more catheters 3100 of the present disclosure.

Mild hypothermia (MH—temperature ˜34° C.) provides cardioprotection and decreased infarct size following MI by reducing myocardial metabolic demand, free radical creation, and platelet aggregation. Clinical translation of these cardioprotective results, however, have not been largely successful because of an inability to locally cool the ischemic region prior to PCI (i.e., inability to cool the ischemic region without first removing the arterial obstruction—which is the dilemma currently facing medical practitioners). Since traditional endovascular methods can only locally cool the ischemic myocardium after but not before PCI, full clinical utility requires a new percutaneous route for local MH delivery to the ischemic region prior to PCI. Unlike the obstructed coronary arterial system, the coronary venous system remains unobstructed and thus has great potential for therapy delivery (retrograde delivery of arterial blood flow with and without MH). Unfortunately, therapeutic retroperfusion has not been adopted clinically because complicated equipment is required to regulate perfusion to prevent damage to the entire coronary venous system when exposed to larger arterial pressures.

To address this limitation, the present disclosure includes disclosure of a novel, catheter-based method of selective auto-retroperfusion (SARP) that regulates the pressure to the venous system (<50 mmHg) to locally deliver cooled arterial blood (MH-SARP) to the ischemic region. Importantly, results from our recent early phase studies using said method have demonstrated remarkable and unprecedented reduction in infarct size (˜93%) in a swine model of anterior LV MI which corresponded with an attenuation of markers for ischemic (cardiac troponin), reperfusion (ST segment depression) and cellular injury (oxygen, glucose and lactate uptake as well as caspase-3 expression). Interestingly, SARP alone also significantly (83%) reduced these indices to near equivalent levels suggesting that the primary benefit may be derived by oxygen delivery without the need for MH. Additional studies to advance the aforementioned results include therapies during longer ischemic and shorter retroperfusion periods while minimizing disruption to clinical workflow, door to balloon time, and overall risk to patients. The present disclosure includes disclosure of a novel MH-SARP or SARP catheter (an exemplary perfusion system 100 of the present disclosure including a catheter 1000) that provides an effective therapy to reduce infarct size and limit RI. The strengths of the MH-/SARP catheter (an exemplary perfusion system 100) include the ability to: (1) deliver localized therapy prior to PCI, (2) deliver therapy without the need or use of complicated, external pumps, (3) quickly deploy therapy (˜5 mins under fluoroscopy), and (4) treat the majority of the STEMI patients that experience RI (≥60% of the 500,000).

An additional embodiment of a perfusion system 100 of the present disclosure is shown in FIG. 27. As shown in FIG. 27, system 100 comprises a first catheter 1000 having a distal end 1004, a proximal end 1002, and defining a lumen 1006 therethrough, wherein at least a portion of first catheter 1000 is configured for insertion into a body of a patient, such as into a patient's heart or a patient's vein, for example. First catheter 1000, after insertion into a patient's vein or heart, for example, is capable of providing arterial blood (which is relatively rich in oxygen and other nutrients) thereto by way of transfer of arterial blood from, for example, a patient's artery, as described below, into a proximal catheter opening 1008, through lumen 1006, and out of distal catheter opening 1010. In such a fashion, for example, a system 100 can be referred to as an autoretroperfusion system 100, noting that no outside pumps are necessary (as the patient's own heart serves as the pump), and due to the retrograde nature of the perfusion with respect to such a use. Exemplary uses, as provided in detail herein, are to provide arterial blood, using system 100, to a patient's femoral vein, internal jugular vein, subclavian vein, and/or brachial cephalic vein. In an exemplary embodiment, first catheter 1000 may be tapered toward distal end 1004 to facilitate insertion into a patient.

In at least one embodiment of system 100, and as shown in FIG. 27, system 100 comprises a coupler 1012 having an outlet port 1013 and one or more additional ports to facilitate connection outside of the patient's body. For example, and as shown in FIGS. 15 and 16, coupler 1012 comprises an inflation port 1014, whereby fluid and/or gas introduced into inflation port 1014 can be used to inflate an expandable balloon 1016 positioned along first catheter 1000 at or near the distal end 1004 of first catheter 1000. As shown in the figures, and in at least one embodiment, an inflation tube 1018 may be coupled to inflation port 1014 at a distal end 1020 (such as shown in FIGS. 15 and 16) of inflation tube 1018, whereby inflation tube 1018 may also have an optional flow regulator 1022 positioned relative thereto to regulate the flow and/or pressure of fluid and/or gas in and out of a lumen 1024 of inflation tube 1018 to inflate and deflate expandable balloon 1016. Inflation tube 1018 may further comprise a proximal connector 1026 configured to receive fluid and/or gas from a fluid/gas source (not shown), whereby proximal connector 1026 can be positioned at or near a proximal end 1028 (such as shown in FIG. 15) of inflation tube 1018, for example. Inflation of expandable balloon 1016, for example, can be used to anchor first catheter 1000 to a desired position within a luminal organ of a patient.

As shown in FIG. 27, for example, a portion of catheter 1000 near distal end 1004, such as between distal end 1004 and balloon 1016, can comprise an atraumatic tip 2700. Atraumatic tip 2700 can have a fenestration pattern, namely a series of one or more openings defined therein, so to reduce pressure therein and/or increase outflow/perfusion. FIG. 28A shows a distal portion of an exemplary catheter 1000 of an exemplary system 100 of the present disclosure, whereby atraumatic tip 2700 is located at a distal portion of catheter 1000, adjacent to distal end 1004. Distal catheter opening 1010 would be located at distal end 1004 of catheter 1000. Atraumatic tip 2700 may also define a fenestration pattern 2702, such as shown in FIG. 28A, comprising a plurality of fenestration apertures 2704 defined on a relative sidewall of catheter 1000, so to allow fluid (such as blood) to flow out of catheter 1000 at said fenestration apertures 2704 as well as distal opening 1010. Fenestration pattern 2702 would be located distal to balloon 1016, as shown in FIG. 28A.

An exemplary coupler 1012 of the present disclosure further comprises an arterial blood port 1030 configured to receive arterial/oxygenated blood from, for example, an arterial blood tube 1032 coupled thereto at or near a distal end 1034 (such as shown in FIGS. 15 and 16) of arterial blood tube 1032. In at least one embodiment, blood flow regulator 1036 comprises a rotatable dial capable of rotation to apply and/or remove pressure to/from arterial blood tube 1032 to regulate the flow and/or pressure of blood through a lumen 1038 of arterial blood tube 1032 and/or to adjust pressure therein based upon identified blood pressure measurements. Such a blood flow regulator 1036, for example, can be used to control blood pressure to limit injury to the patient's luminal organs (such as the patient's venous system and/or myocardium) and/or to minimize potential edema with respect to the same luminal organs. Arterial blood tube 1032 may further comprise a proximal connector 1040 configured to receive arterial/oxygenated blood from a blood supply, whereby proximal connector can be positioned at or near a proximal end 1040 of arterial blood tube 1032, for example. Exemplary systems 100 of the present disclosure may include one or more additional features such as shown in FIGS. 15-17 and described herein.

FIG. 27 also shows how portions of system 100 can have different sized tubular elements (catheter elements). For example, and as shown in FIG. 27, system 100 can comprise a catheter 1000, whereby catheter 1000 has one or more segments, such as, for example, a first segment 2710, a second segment 2712, a third segment 2714, a fourth segment 2716, and so forth (or fewer or more segments), whereby each successive segment may be smaller (smaller diameter) than its preceding segment. For example, first segment 2710 may be the largest segment, such as being 13Fr, second segment 2712 may be smaller (such as 12Fr or 11Fr), third segment 2714 may be smaller (such as 11Fr or 10Fr), and fourth segment 2716 may be smaller still (such as 10Fr or 9Fr), as may be desired.

FIG. 28B shows a component diagram of portions of an exemplary system 100 of the present disclosure. As shown therein, an exemplary system 100 of the present disclosure may comprise and/or be coupled to, a regional hypothermia system 4000, such as generally referenced herein, which is configured to connect to other portions of system 100 and cool a fluid, such as blood, flowing therethrough. Regional hypothermia system 4000 may directly connect to an arterial blood tube 1032 and to a catheter 1000 (such as a MH-SARP catheter), as referenced herein, or may indirectly connect to arterial blood tube 1032, catheter 1000, and/or other portions of system 1000, by way of mild hypothermia (MH) quick connector 2800, as shown in FIG. 28B. MH quick connector 2800, as shown in FIG. 28B, is configured to couple to, for example, arterial blood tube 1032, catheter 1000, and/or other portions of system 1000, including regional hypothermia system 4000 (shown as “cooling system” in the figure). MH quick connector 2800 is configured to allow blood to flow therethrough, whereby the blood can be cooled using regional hypothermia system 4000. In at least one embodiment, and such as shown in FIG. 28B, regional hypothermia system 4000 comprises an outlet 2850 and an inlet 2852, whereby a cooling product 4004 can flow from regional hypothermia system 4000, through outlet 2850, into MH quick connector 2800, and out of MH quick connector 2800 into inlet 2852 of regional hypothermia system 4000, so that cooling product 4004 can cool blood flowing through MH quick connector 2800.

MH quick connector 2800, in various embodiments, may comprise a coolant inlet 2810, a coolant outlet 2812, and a reservoir 2814, such as shown in FIG. 28B. Coolant inlet 2810 of MH quick connector 2800 is configured to couple or otherwise connect to outlet 2850 of regional hypothermia system 4000, and coolant outlet 2812 of MH quick connector 2800 is configured to couple or otherwise connect to inlet 2852 of regional hypothermia system 4000, so that, for example, a cooling product 4004 can flow from regional hypothermia system 4000, through outlet 2850, into inlet 2810 of MH quick connector 2800, through reservoir 2814, and out of outlet 2812 of MH quick connector 2800 into inlet 2852 of regional hypothermia system 4000 (such as shown in FIG. 28B by way of the arrows adjacent to coolant inlet 2810, reservoir 2814, and coolant outlet 2812), so that cooling product 4004 can cool blood flowing through MH quick connector 2800. In view of the same, blood can flow, for example, from arterial blood tube 1032, into a blood inlet 2820 of MH quick connector 2800, through a lumen 2824 of MH quick connector 2800, and out of a blood outlet 2822 of MH quick connector 2800 into catheter 1000 (such as by way of a proximal connector 1040 or other connector directly or indirectly coupled to catheter 1000), while a cooling product 4004 can flow from regional hypothermia system 4000, through outlet 2850, into inlet 2810 of MH quick connector 2800, through reservoir 2814, and out of outlet 2812 of MH quick connector 2800 into inlet 2852 of regional hypothermia system 4000, so that cooling product 4004 can cool blood flowing through MH quick connector 2800.

FIG. 28C shows a diagram of how a MH quick connector 2800 of the present disclosure would be used with a mammalian body (a patient 2875, for example). As shown in FIG. 28C, MH quick connector 2800 could be used by way of being connected to an arterial blood tube 1032 and a catheter 1000 (such as a MH-SARP catheter, as referenced herein), so that arterial blood can flow from the arterial blood tube 1032, into MH quick connector 2800 (while then being cooled using a regional hypothermia system 4000 as referenced herein), and into catheter 1000 and ultimately to an organ of interest, such as the heart 2880, for example, for treatment as referenced herein.

As noted above, STEMI is the most serious form of ACS and places a significant financial and clinical burden on the U.S. healthcare system. Over one million ACS events occur each year with approximately 500,000 of these classified as STEMI resulting in myocardial damage and ST segment elevation. While STEMI treatment may involve thrombolytic and/or PCI therapy, numerous studies have shown that reperfusion via PCI (e.g., balloon angioplasty, stenting, thrombectomy) results in lower reinfarction rates, smaller infarct sizes, less short-term mortality, and less stroke compared to pharmacologic therapy alone. The American College of Cardiology (ACC) and American Heart Association (AHA) recommend PCI therapy within 90 minutes of patient presentation to the hospital (i.e., 90-minute door to balloon time). This recommendation is based on numerous studies showing shorter reopening times result in improved short-term and long-term mortality, reduced infarct size, and increased LV function.

Despite efforts to support these patients, in-hospital and post-discharge STEMI fatality rates remain high (both ˜10%) with STEMI mortality directly relating to the total infarct size. Up to 50% of the total myocardial damage may be related to the restoration of blood flow to the artery following PCI (i.e., reperfusion injury or RI). Microvascular obstruction (no re-flow phenomenon), tissue necrosis and apoptosis, myocardial stunning, endothelial injury, LV remodeling, diminished LV function, and increased mortality are all linked to RI. The prevalence of RI is high and remains a significant complication associated with PCI even in seemingly straightforward cases. For example, 60% of patients with no angiographically visible perfusion defect following PCI (i.e., TIMI flow=3) experience no re-flow phenomenon. Even after seemingly appropriate PCI therapy, a significant percentage (˜25%) of surviving STEMI patients eventually develop heart failure (HF). Due to the large number of ACS events and RI, the annual U.S. cost for MI treatment is substantial (˜$31B) which demands novel approaches to prevention and/or treatment options.

Currently (and prior to the present disclosure), there is/was no widely accepted clinical method for RI prevention or treatment. Many pharmacological therapies have been investigated in animal and clinical settings to target fundamental mechanisms related to RI injury, including calcium overloading, reactive oxygen species, and myocardial metabolism. To date, nearly every pharmacological therapy has failed to show clinical translation for limiting RI and/or improving outcomes. Other therapies, such as ischemic pre- and post-conditioning have been investigated as possible options to prevent and/or limit RI. Pre-conditioning is impractical, however, because it requires knowledge of the ischemic event prior to its occurrence, while post-conditioning requires additional gradual balloon inflations/deflations which adds time to the procedure. Most importantly, the various therapies have largely failed clinical translation because of an inability to locally deliver therapy to the ischemic region prior to the removal of the arterial obstruction.

The present disclosure includes the first know methods to use SARP alone as well as MH-SARP to attenuate RI in an unprecedented manner in swine. MH (˜34° C.) without SARP has been investigated, however, as a therapy option for RI. The cardioprotective nature of MH is related to diminished myocardial metabolic demand and free radical creation (cardiomyocyte and/or arterial endothelial). Although very effective in animal studies, MH has failed to translate clinically since the arterial obstruction blocks delivery of MH to the ischemic region prior to PCI (i.e., MH is most effective prior to reperfusion and not after). Hence, a common limitation for therapies which target RI is deliverability. Retroperfusion provides an option to delivery therapy via unobstructed coronary venous circulation. Complicated pumps and equipment, however, have hindered implementation (see Innovation below). Importantly, the current approach addresses these hurdles of delivery via auto-retroperfusion to selectively deliver cooled, oxygenated blood to the ischemic region prior to removal of the arterial obstruction in order to reduce RI and hence infarct size.

The MH-/SARP systems of the present disclosure have enormous potential as they address current limitations in the treatment of a significant number of STEMI patients. The catheter system (system 100) can directly benefit the patient by sustaining viable myocardium to prevent progression to HF. Reductions in complication rates under hospitalization as well as long-term patient support will also greatly decrease healthcare costs. The ability of the MH-/SARP system to deliver retroperfusion is highly desirable and a key requirement for the growing market of therapeutics which are limited by a lack of route for administration during a coronary artery occlusion. The simplicity of the MH-/SARP is also highly attractive as it does not disrupt clinical workflow or require cost prohibitive equipment while providing the critical benefit of salvaging myocardial mass at a low cost of goods (COGS at <$100, for example). These features allow the MH-/SARP to serve as either an isolated therapy (i.e., SARP) or in combination with MH, cell or drug delivery.

As previously referenced herein, the present disclosure includes disclosure of a novel SARP catheter (an exemplary perfusion system 100 including a catheter 1000) configured to provide localized therapy (+/−MH) using retroperfusion to the ischemic region prior to PCI to prevent/reduce RI. This therapy is delivered to the region of interest through selective engagement of the coronary venous anatomy near the site of the arterial obstruction using a novel percutaneous venous catheter (an exemplary perfusion system 100 including a catheter 1000) with retrograde perfusion of the patient's own arterial blood (with or without cooling) through the catheter (an exemplary perfusion system 100 including a catheter 1000). The perfusion parameters are intrinsically regulated by the catheter design which simplifies the delivery of therapy (and minimizes cost) by not requiring an external temperature or pressure controller. Both the delivery methods (SARP) and the catheters (exemplary perfusion systems 100 including catheters 1000) of the present disclosure provide innovations that are unique for the delivery of the MH therapy, but also show adaptability to provide additional therapy options for this and other patient populations.

One of the most innovative and clinically significant feature of the present disclosure is the fact that SARP therapy can be delivered prior to PCI in the presence of coronary artery stenosis. SARP+/−MH is possible because of the distinctive characteristics of the coronary venous system that provides a suitable network for local retrograde perfusion during arterial obstruction. The coronary venous system consists of an elaborate network of interconnecting and redundant pathways which make retroperfusion possible. The coronary venous system consists of (1) inter-venous connections, (2) Thebesian-sinus connections, and (3) a venous plexus. Without these interconnections and redundant pathways, drainage would only occur directly into the coronary sinus making retroperfusion impractical (i.e., would cause flow stagnation). The coronary venous system is interconnected and does not consist of a single venous outlet, however, thus making retroperfusion safe and without the possibility of flow stagnation. These features have been specifically highlighted by the extensive coronary venous anatomical reconstructions completed by our group.

Retroperfusion provides benefit for effective therapy delivery to the myocardium due to the extensive surface area and exchange capabilities across the venule network. Considerable temperature and oxygen exchange can occur at the venule level due its large surface area (six times the surface area of arterial capillaries) and small wall thickness (only twice the thickness of capillaries). Besides therapy delivery, we hypothesize that SARP reduces the production of toxic reactive oxygen species (ROS) that lead to mitochondrial dysfunction (arterial endothelial and cardiomyocyte), calcium overload, and reduced NO bioavailability (contributors to RI) which in turn promotes inflammation, microcirculatory plugging and cardiomyocyte damage during washout as well as edema. Finally, coronary veins do not have atherosclerosis which provides a non-diseased network for therapy delivery. Thus, there is a strong anatomical and physiological basis for coronary venous retroperfusion to deliver therapy (i.e., no venous atherosclerosis, reduced ROS signaling, venous interconnectedness, large venous surface area, thin-walled vessels, etc.).

SARP provides a novel and clinically acceptable method for delivery of MH that eliminates problems associated with traditional retroperfusion. Although retroperfusion is used routinely in surgery for cardioprotection of the arrested heart, it has not gained routine clinical adoption in non-surgical applications because of the complicated and cumbersome equipment needed for the therapy (e.g., one or more pumps that perform synchronized occlusions of the coronary sinus to elevate coronary venous pressure and/or perform active pumping action to promote retrograde blood flow). In contrast, SARP does not require complex pumps, but instead uses auto-perfusion of the patient's own arterial blood. A quick connection between an arterial source and the proximal end of the SARP catheter (an exemplary perfusion system 100 including a catheter 1000) allow for the patient's own arterial pressure to be the driving force for perfusion. The auto-delivery of MH using the patient's own blood provides an added two-in-one benefit to the patient (i.e., both MH and oxygen therapy are delivered directly to the ischemic region). Based on proximal catheter temperature measurements when delivering MH, the user can adjust the external cooling circuit using a simple temperature controller. Also, SARP does not require total occlusion of the coronary sinus as done with traditional retroperfusion, but instead provides a method of local therapy delivery without coronary venous outflow congestion (e.g., selective LV anterior wall perfusion).

The MH-SARP system of the present disclosure provides an unprecedented innovative therapy option to substantially reduce RI that provides benefits over previous pharmaceutical and device approaches. These benefits include: (1) Therapy to the ischemic region prior to and not after PCI, thus requiring no removal of the arterial obstruction prior to usage, (2) Two-in-one therapy delivery of both MH and oxygen/nutrients, (3) Ability to wash out harmful waste products and decrease plugging and trapping, (4) Simple therapy without the need for complex pumps (auto-perfusion), (5) Localized therapy delivery only to the region of interest (selective-perfusion) via established and easily accessible main coronary venous anatomy, (6) Minimally invasive (percutaneous), (7) Easy to use (quick connections), (8) Ability to deliver multiple therapies (e.g., thrombolytic, gene therapy, etc.), and (9) Ability to extend the therapy to other patient groups (e.g., cardiogenic shock).

An exemplary embodiment of the MH-SARP system of the present disclosure comprises three components: (1) the SARP catheter (an exemplary perfusion system 100 including a catheter 1000), (2) the arterial sheath, and (3) the MH quick-connector. An exemplary SARP catheter (an exemplary perfusion system 100 including a catheter 1000), as shown in FIGS. 15 and 27, may comprise a 9-13Fr diameter, 120 cm long device intended for 0.035″ over-the-wire access of the coronary venous system through a femoral vein approach. The distal 6 cm of the catheter is atraumatic, soft, and has a 9Fr outer diameter for safe and effective delivery given the large size of the coronary venous anatomy. The catheter increases in size from 9Fr at the last 6 cm of the distal end to 13Fr at the proximal end and is introduced through a 14F femoral venous sheath. The catheter length (120 cm) allows for femoral access to the coronary sinus. The inner diameter of the catheter has been maximized to allow for optimal delivery of retroperfusion therapy. The catheter is radiopaque with special markers placed every 5 mm apart at the distal end to aid in navigation and placement, and includes a series of distal side holes to maximize flow delivery. A soft, compliant balloon (length/diameter ˜1 cm) is placed 2 cm away from the distal tip, which is inflated just prior to retroperfusion therapy and used to occlude the vein of interest to prevent anterograde flow while allowing retrograde flow through the central catheter lumen. This catheter is easy to navigate and place in the coronary venous anatomy.

Three features critical for catheter function exist at the proximal device end. The first feature is a port used for balloon inflation that allows for occlusion of the vein and for selective auto-retroperfusion through the center lumen of the catheter. The second feature is a blood source connector that provides blood and MH access to the central catheter lumen. The blood source is obtained from a separate 6Fr high-flow side arm arterial access sheath placed in the femoral artery. Future studies will incorporate the high-flow port onto a slightly larger 7Fr or 8Fr arterial sheath that would be used for PCI, i.e. only one additional venous sheath would be required for SARP therapy. This connector has a standard luer lock that attaches to the arterial blood source via the MH quick connector (see more quick connector details below). The third proximal feature is a port connected to the inner catheter lumen that is used for 0.035″ or 0.018″ over-the-wire exchange. Once a 0.035″ guidewire is placed in the proper location in the coronary venous anatomy, the SARP catheter (an exemplary perfusion system 100 including a catheter 1000) is tracked over-the-wire, and the guidewire is removed. The port can be used for the placement of a 0.014″ pressure guidewire to the distal end of the catheter. The 0.014″ guidewire is very small relative to the large diameter catheter (will not impact the therapy delivery) and will be used to verify the pressure and flow at the distal end of the device (note the temperature measurements will be made using a thermocouple described in the next sections placed directly in the subendocardium). The results of early studies show that the elevated pressure of the delivered therapy did not exceed safety thresholds (i.e. <60 mmHg). Thus, the design of the catheter and extent of the fluid path provide an intrinsic pressure control mechanism.

The SARP catheter (an exemplary perfusion system 100 including a catheter 1000) receives the MH fluid source via the arterial sheath and quick-connector. The arterial sheath is a standard 6Fr diameter that is placed in the femoral artery using standard interventional techniques. A high flow side arm with a luer lock connector on the arterial sheath joins to the MH quick-connector which then connects to the SARP catheter (i.e., series connection between the arterial sheath, the MH quick-connector, and the SARP catheter). The MH quick-connector provides two functions: (1) an extension tubing to connect the arterial source to the SARP catheter (an exemplary perfusion system 100 including a catheter 1000) and (2) cooling of the arterial blood (i.e., MH). The quick-connector is a 6Fr diameter, 30 cm long flexible tubing with luer connections and a Peltier cooling system with a 316 stainless steel heat-exchanger that allows for a completely sterile and isolated fluid loop without the risk of contamination via fluid/gas leak. The MH quick-connector also contains a non-contact, integrated thermocouple at the outflow connection which provides feedback to the MH system for temperature adjustment as needed. Consequently, a known relationship between flow rate and temperature drop at the outflow section of the cooling segment can be used adjust the degree of coolant wattage in order to achieve controlled delivery of MH.

The benefit conferred by the MH-/SARP will supersede any modest disruption to clinical workflow and will integrate well with the PCI procedure to restore coronary blood flow. It is anticipated that retroperfusion will remain an effective therapy when delivered over a minimum 10 minute duration in parallel with treatment of a coronary obstruction. (retroperfusion would continue until opening of the coronary obstruction). The IC can independently deliver the SARP catheter and initiate retroperfusion prior to beginning of PCI. Retroperfusion can then occur in parallel with PCI until opening of the coronary obstruction. This integration into workflow can be assessed separately by different ICs. As identified by our initial results, it takes ˜3 minutes to achieve a reduction in subendocardial myocardial temperature (FIG. 30) and ˜15 min for normalization of ST segment depression (FIG. 32A). Including the time to access the coronary vein (5 min), we project the total time allowed for retroperfusion therapy to be near maximum effectiveness is within the average time from arterial access to balloon angioplasty (10-15 minutes). Hence, we expect that even at a minimal 10 minutes of retroperfusion a significant benefit will be conferred. Future studies will utilize a longer ischemic period (90 minute), and minimal 10 minute retroperfusion period to challenge therapeutic differences between normothermia and hypothermia retroperfusion. Although it has been shown that a 10 minute difference in door to balloon time does not affect mortality, it is important to determine the efficacy of the approach and integration into clinical workflow in order to minimize patient risk; i.e., maintain the same door to balloon time while decreasing the severity of infarction. Achieving these endpoints are also critical for clinical and commercial adoption.

Initial study data obtained utilized a 30 minute period of LAD occlusion established proof of concept and identified the extent of myocardial preservation possible and metabolic impact of MH-SARP and SARP therapy. Although both significantly reduced infarction (gold standard for assessing therapy) by an unprecedented degree, no differences were observed between normothermia and hypothermia. The question that remains is whether or not a benefit of the hypothermia may be distinguished when challenged by more translatable conditions; i.e., longer occlusion time and shorter therapeutic period. The need to layer MH on top of SARP is also achievable with an approved bedside cooling system.

Based on the knowledge of the parameters (pressure, flow, temperature) required to achieve MH-SARP (as identified in our initial results), additional studies can be performed to test the ability of SARP and MH-SARP to limit RI and reduce MI size in animals after 90 minutes of STEMI followed by PCI (i.e., implanted hydraulic occluder followed by deflation to mimic PCI for coronary obstruction). For example, one experimental cohort would receive MH-SARP for 10 minutes prior to pseudo-PCI, while another would be SARP alone for 10 minutes prior to PCI. Data will be compared to each other as well as against control animals. To determine the effectiveness of the MH therapy, a comparison can be made for total infarct size and other RI parameters between the MH-SARP and sham control groups. These additional RI indices will be pursued to identify the mechanism underlying the observed efficacy of SARP and MH-SARP (i.e., oxidative and apoptotic pathways based on phase I results). Said studies further validate the mechanism of the SARP catheter (an exemplary perfusion system 100 including a catheter 1000) to reduce RI injury and myocardial infarct size under standard clinical workflow conditions. Additional in vivo studies that recreate the pathology, anatomy, and treatment workflow while assessing acute and chronic indices of RI and infarction to determine the cellular mechanism of therapy can also be performed.

Animal studies involve the administration of oral amiodarone for 3 days prior to initiation of the study procedure. Once anesthesia is induced, the animals are be intubated and the occluder inflated. The IC will then obtain right femoral artery access with a 6Fr sheath. Sham access to the LAD artery can be achieved with a 0.014″, 190 cm workhorse guidewire and a 6Fr, 100 cm HS guidecatheter to mimic normal approach for a diagnostic angiogram and subsequent PCI. Contrast can be injected to confirm occlusion. Next, a 14F sheath can be placed in the right femoral vein and a 7F high flow sheath placed in the left femoral artery for SARP catheter delivery and blood harvest, respectively. The SARP catheter (an exemplary perfusion system 100 including a catheter 1000) can then be advanced over a 0.035″ or 0.018″ guidewire which will be exchanged for a 0.014″ Volcano ComboWire (an exemplarty wire) once the SARP catheter is in position. The ComboWire can provide feedback about the pressure and flow measurements at the distal catheter end (i.e., tip flow must be >30 ml/min and pressure <50 mmHg). MH therapy can be delivered in the experimental group 2 until a temperature of 34° C. is achieved in the distal ischemic subendocardium via thermocouple/O₂ ⁻ probe from the right CFA (note: the system and experimental approach are adaptable to either leg). The custom thermocouple is embedded into an 18g needle at the end of a catheter which will also be used as an electrode to measure superoxide production. The SARP balloon can be inflated in the proximal portion of the LAD vein (<10 minutes after arterial access is established), and SARP therapy will be delivered for a total of 10 minutes prior to deflation of the LAD occluder (i.e., 90 minutes of LAD artery occlusion for STEMI with 10 minutes of MH-/SARP in the last 10 minutes with the LAD still occluded). This approach assures a constant duration of occlusion between cohorts. MH-/SARP will be achieved by attaching the left femoral artery blood source to the SARP catheter (an exemplary perfusion system 100 including a catheter 1000) via the pre-cooled and flushed MH quick-connector which will be slowly opened to maintain a safe perfusion pressure (<50 mmHg). Venous blood sampling at appropriate pre- and post-therapy intervals throughout protocol will be used to assess markers of RI and infarction, while additional measurements including the 12-lead ECG and 2D/3D TEE echocardiography to assess LV function. LAD occluder deflation (i.e. PCI) will occur 90 minutes after occlusion in all cohorts. Animals can then be recovered for 8 weeks with follow up ultrasound and blood samples every two weeks.

Following euthanasia, the extent of the RI can be examined in each heart through a series of infarct size, histological, immunohistochemistry and protein isolate analyses. The goal of serological and post-mortem tissue analysis is to assess the mechanism(s) by which SARP and/or MH-SARP may reduce RI and infarction. Based on our initial results which correlated reduced oxygen uptake, onset of anaerobic glycolysis, and inhibition of apoptosis with significant reductions in infarction we believe/understand that the underlying mechanism is oxidative. Specifically, a reduction in ROS-dependent membrane damage including mitochondrial dysfunction, increased intracellular calcium, and decreased nitric oxide (NO) would attenuate apoptosis which is largely an energy dependent pathway. Thus, a reduction in metabolism with MH and hence, ROS production would further reduce the benefit of SARP which is in line with our initial results.

Regarding infarct analysis, and in addition to serum cTnI venous samples, the area at risk and infarction can be identified in all hearts by an injection of 5% Evans blue dye (0.5 ml/kg) into the left atrium via the left internal thoracic artery just prior to euthanasia of study animals. Heart slices (8 mm thick) taken of the LV parallel to the atrioventricular groove can be incubated in triphenyl tetrazolium chloride (TTC), which converts dehydrogenases to a red pigment in viable myocardium and leaves necrotic myocardium unstained because of the loss of dehydrogenases. The areas of viability and infarction will be calculated on enlarged photographs using the computer analysis software Sigma Scan Pro 5 (Systat Software, San Jose, Calif.).

Regarding superoxide production, oxygen-dependent free radical production can be assessed during the occlusion procedure using a pre-calibrated sharp electrode technique. A sensing electrode can be run parallel to a thermocouple and imbedded inside a needle fixed to the end of a catheter similar to our initial study approach. The electrode can be connected to an Apollo 4000 (World Precision Instruments) and inserted percutaneously into the myocardium in the ischemic LAD perfusion territory. Each electrode will be calibrated in vitro with known concentrations of O₂— and the current recorded during the in vivo experiments.

Regarding histology and immunohistochemistry studies, ischemic and non-ischemic LV regions can be perfusion-fixed in 4% paraformaldehyde and prepared for histological and immunohistochemistry analysis. Paraffin-embedded sections will be prepared for RI/MI evaluation and immunohistochemistry determination. Specifically, redox enzymes will be immunostained to distinguish between arterial and venous endothelial xanthine oxidase, cytochrome oxidase and cyclooxygenase expression. These additional tests can help to determine variability in ROS tolerance between the two vascular systems which may support why venous retroperfusion can reduce RI and infarction vs. arterial reperfusion which potentiates it.

Regarding the evaluation of NO and the fluorescent evaluation by diaminofluorescein-2 diacetate (DAF-2DA), and to assess inherent differences in local NO bioavailability which can bind to superoxide, the tissue can be incubated in PSS with DAF-2DA (10 μM) at 37° C. in a dark box for one hour. The tissue can then be washed and cryo-sectioned, and the fluorescent intensity will be determined by fluorescent microscope (Eclipse TE300, Nikon).

Regarding the expression of eNOS, and to determine differences in venous and arterial eNOS expression, protein extracts from tissues can be fractionated on 10% SDS-PAGE gel, transferred onto a polyvinylidene difluoride membrane, and target primary antibodies (eNOS) and anti-phosphorylation of eNOS (index of activity) can be measured. Blots will be incubated with horseradish peroxidase-conjugated secondary antibody and signal detected by enhanced chemiluminescence and normalized by (3-actin.

Regarding Apoptosis, the identification of apoptotic cells can be performed using a fluorescent In situ Cell Death Detection Kit (Roche, Indianapolis, Ind.). Caspase-3 and poly(ADP-ribose) polymerase (PARP) can be quantified via western blot assay. Tissue slides can be incubated with a TUNEL reaction mixture and nuclei will be stained with DAPI (Invitrogen, Grand Island, N.Y.). The density of TUNEL+ cells can be quantitatively assessed and expressed as cells/mm.

Regarding calcium and mitochondrial transition pore staining, and to determine the pathway for apoptosis and differences in mitochondrial calcium loading, a BioVision permeability transition pore assay kit can be used to assess increases in mitochondrial free Ca²⁺ (Rhod2) and inner membrane permeabilization (calcein).

Regarding statistical analysis, the time to coronary venous access, retroperfusion circuit setup, SARP balloon inflation, ST segment normalization, temperature reduction and cellular indices of RI can be expressed as mean±SD. Significance of the differences between three groups (control, SARP, MH-SARP) can be evaluated by two-way ANOVA or repeated measures where appropriate. The results can be considered statistically significant when p<0.05 (2-tailed). Safety can be determined by incidence of arrhythmia, interstitial edema, and biomarkers of inflammatory and reperfusion injury. Infarct size can be determined directly by TTC staining and image processing. Non-inferiority of SARP to MH-SARP can be determined by comparing time to initiate therapy, ST segment changes from the beginning of balloon inflation, number and severity of arrhythmias, ease of integration as determined by qualitative scoring by interventionalists and overall infarct size. Repeatability and control over efficacy can be determined based on coefficient of variation (SD/mean) and used to assess the ability to integrate efficiently into standard clinical workflow.

The aforementioned studies should generally show significant reductions in infarct size and indices of RI in SARP and MH-SARP vs. control animals. The troponin levels, degree of ST segment depression, number of PVCs as well as the presence of preserved cell viability can be comparable between the two groups with only moderate improvement in MH-SARP vs. SARP alone. A longer recovery period (8 vs. 4 weeks) may be expected, which demonstrates preserved EF and myocardial strain between MH-SARP and SARP cohorts which are in contrast to control group with MI that demonstrates early signs of HF and large area of infarction. Although some distinction between MH-SARP and SARP may be noted in cellular endpoints (i.e., oxidative and apoptotic pathways) the presiding data are functional endpoints. The achievement of MH (<35° C.) in the distal ischemic region soon after the start of MH-SARP (along with secondary measurements) demonstrates more rapid resolution of the ischemia as supported by ST segment elevation. Investigations into the underlying mechanisms support that in the presence of an alternative source of ATP as from glycolysis, then necrosis is prevented and a caspase-dependent apoptosis occurs secondary to release of proapoptotic factors from the mitochondrial intermembrane space after outer membrane rupture. We expect these findings to correspond with a significant reduction of ROS in treatment vs. control animals.

While our initial tests show the ability of the MH-SARP catheter (an exemplary perfusion system 100 including a catheter 1000) to deliver therapy in an anterior LV occlusion, other regions of the heart (such as the LV lateral wall) can also be treated with SARP through cannulation at the level of the great cardiac vein instead of the LAD vein. Limitations may exist surrounding delivery of SARP if arterial pressure is too low (pharmacologically prevented) to provide sufficient gradient across the catheter to drive flow then perfusion may be reduced below the threshold for efficacy. However, the resistance to distal catheter outflow is in part based on the contractile status and therefore tissue pressure of the heart as represented by arterial pressure. Hence, the pressure drop across the catheter is constant based on the length and diameter, and the gradient between arterial inflow and coronary venous outflow remain relative which provides a continuous driving force for blood flow. Alternatively, the catheter can be advanced further to optimize the volume of blood flow delivered per unit mass of ischemic tissue. There may also exist large variability in the times recorded for initiation of SARP or MH-SARP due to early experience and training on delivery approach required. While some of this will be eliminated having selected ICs proficient in coronary venous access and first providing training on a bench setup, any observed difference between first and last cases will in fact be informative in terms of usability as well as the number of roll out cases that may be needed for a clinical study. Additional inflammatory-dependent sources for ROS production may contribute to RI. However, our initial studies were negative for IL-1, IL-6 and TNFα. Regardless, additional redox metabolites such as hydroxide and peroxynitrite can be considered using a similar sharp electrode technique. Lastly, the current approach requires the IC to place an additional 6Fr sheath with a high flow side-arm. We anticipate that future studies will eliminate this need by using a single 7Fr or 8Fr standard access sheath.

Auto-retroperfusion+/−MH is a highly novel approach to reduce infarct size and RI in patients, which carries inherent risk. Additional studies are being performed to verify the safety of the SARP system under GLP standards. In these additional study animals, the ability of the final catheter prototype design to deliver retroperfusion as required for normalization of ECG and reductions in infarct size will be assessed. Specifically, controlled SARP delivery without any adverse events (safety) as a result of incorporating the device into standard procedural workflow will be the endpoint. The study will involve a total of 18 swine of either sex as recommended for FDA/IRB submission. The animals will be divided randomly into Groups I through IV. Group I will consist of SARP (n=6) treated swine with anterior LV STEMI, similar to Aim 1. Group II (n=3) will serve as the control for this group which will only have the LAD occlusion and sham access of the catheter into the coronary vein and delivery of LAD balloon but no retroperfusion or balloon inflation, respectively. Group III (n=6) will be a SARP treated swine with anterior LV STEMI, but no LAD occlusion. Group IV (n=3) will serve as the control for this group and will not have SARP or LAD balloon occlusion. Groups III and IV will have a sham balloon delivery (no inflation), however, in order to increase the numbers used for comparing time to inflation+/−SARP (Group I). This distribution of cohorts minimizes the number of swine needed while maintaining the appropriate controls. Importantly, group III represents the worst case scenario where there is maximum resistance to retroperfusion outflow and hence, greatest chance for interstitial edema and damage. This cohort challenges the potential injury response to clearly demonstrate safety under worst case conditions. For groups I and II, the LAD will be occluded for 90 minutes with SARP initiated 10 minutes prior to deflation (group 1) or no SARP administered (group II). All experimental groups will be recovered for 4 weeks and histopathology assessed in comparison to non-retroperfused (n=3) or non-retroperfused LAD occluded controls.

The primary endpoint of safety will be determined by the absence of arrhythmias as recorded by a 12-lead ECG during SARP engagement, perforations (venous or cardiac) and adverse histopathological results. Each of the two groups will have a sham-operated control which will undergo the identical interventional procedures except that the coronary artery or vein will only be accessed and no balloon inflated or SARP initiated. In addition to freedom of adverse events, histopathology will serve as a key endpoint for safety. In particular, the myocardium will be examined by an independent board certified pathologist for signs of atypical inflammation, hemorrhagic infiltrate, or necrosis directly resulting from the retroperfusion. Study groups will not be identified to the pathologist; i.e., a completely blind histo-pathological read. X-ray exposure will also be compared. The performance of the catheter will also be assessed based on ability to reach targeted location indicated on coronary venogram which will also serve as an index of feasibility.

The extent of edema and hemorrhage will be measured by the wet/dry ratio. Transmural plugs will be subdivided into thirds to separate the endocardium, midwall and epicardium. The weight of each tissue will be measured before and after drying. The LV territory will then be fixed with glutaraldehyde. The ultrastructure of the microvessels and LAD vein will be evaluated using standard histological methods. Myocardial tissue samples from the free LV wall (epicardium, midmyocardium and endocardium) will be embedded in JB-4 solution, cut (3 □m thickness) with glass knives, stained with Toluidine Blue, and prepared for microscopic visualization of blood vessels and myocytes for assessment of damage due to edema or hemorrhage. Additional safety and secondary feasibility measurements include the time from access to SARP initiation. It is highly important that SARP therapy does not significantly prolong the procedural time.

Time to deliver, duration of preparation during circuit connection and wet/dry ratio will be expressed as mean±SD. Significance of the differences between two groups (SARP occlusion vs. SARP) will be evaluated by two-way ANOVA or repeated measures where appropriate. The results will be considered statistically significant when p<0.05 (2-tailed). Safety will be determined by incidence of arrhythmia, retroperfusion-dependent inflammatory scoring and degree of edema. Feasibility will be determined based on minimal difference in time to balloon delivery with SARP (Groups 1 and 3) vs. balloon alone (Groups II and IV). Repeatability will be determined based on coefficient of variation (SD/mean) for time to initiate SARP which will be used to assess the level of feasibility and integration into workflow (compared to sham balloon procedures).

The completion of these animal studies is expected to confirm the safety and feasibility of the SARP system. No safety risk is expected during SARP usage (i.e., no arrhythmias, tissue trauma or death) as supported our initial findings. The confidence that no adverse cardiovascular events or damage will occur during SARP usage as demonstrated in our original studies is based on the fact that: 1) Outflow catheter pressure will remain below the safety threshold for causing damage 2) Explant of retroperfused hearts will not show any signs of hemorrhagic infiltrate or tissue trauma (similar to our initial studies), 3) Normalization of ECG attenuates the propensity for adverse events and arrhythmias during retroperfusion, 4) Number of arrhythmias during reperfusion will be reduced by SARP delivery of nutritive flow and 5) SARP maintains routine safety guidelines for coronary venous interventions can be easily integrated into the clinical workflow. The feasibility of the SARP will be further supported by negligible differences in the time to deliver PCI balloon vs. balloon+SARP. Efficacy (tertiary) of the SARP catheter system to reduce infarct size and RI will be supported by the histopathology qualitatively noted in control vs. normal SARP treated hearts. We anticipate that the oxygen delivered by the SARP will reduce various indices of RI and long-term cardiac dysfunction. We do not anticipate any issues, limitations or safety concerns associated with delivery of the SARP catheter itself.

Ex-Vivo Testing. Initial studies on bench were focused on determining the correct relationship between perfusion temperature, epicardial temperature and subendocardial temperature. To determine the relationship between mild hypothermia retroperfusion temperature and transmural left ventricular (LV) tissue temperature, a beating heart preparation was utilized. Swine hearts (n=5) were harvested under deep anesthesia and perfused with heparinized cardioplegia. LV wedge preparations were dissected from hearts and both the left anterior descending artery (LAD) and the great cardiac vein (GCV) were cannulated. LV wedges were perfused and submerged with warm (37° C.), oxygenated Tyrode's solution at a pH of 7.35±0.05. Thermocouples were placed in numerous locations, including the following: 1) Surrounding solution of the tissue chamber, 2) Inlet cannulas, 3) Subenodcardium (apical, mid, and basal), and 4) Subepicardium (apical, mid, and basal). The Tyrode's solution in the tissue chamber was maintained at 37° C. with a heating bath circulator. LV wedges were endocardially paced (PowerLab 16/30, ADInstruments, Colorado Springs, Colo.) at 1 Hz at twice the diastolic threshold and Ag/AgCl pellet electrodes (WPI, Sarasota, Fla.) monitored the far-field ECG. Tissue was initially perfused via the LAD (37° C.) under constant pressure (100 mmHg) and allowed to stabilize for 30 min. Antegrade perfusion was switched to retrograde perfusion and 27.5° C. Tyrode's solution was perfused via the GCV under moderate pressure (50 mmHg). Retrograde perfusate was allowed to steadily warm to 34° C. over 80 min.

As shown in FIG. 29B, a relationship between perfusion temperature at the inlet of the vein and the transmural temperature gradient was established. Specifically, when the solution leaving the GCV cannula is 30-32° C., the subepicardium is ˜2° C. cooler than the subendocardium. Further, the apical subepicardium was modestly cooled compared to the basal and mid myocardium. For the same 30-32° C. solution leaving the GCV cannula, basal subepicardium tissue is ˜1° C. cooler than apical subepicardium tissue. Although these results are critical to understanding the hypothermic regional distributions, however, it did not describe the relationship between the external cooling system and thermal loss as blood is retroperfused. Thus, additional bench experiments were performed to identify the amount of cooling required and overall flow circuit design in order to achieve the target cannula temperature identified in the wedge preparation.

Our preliminary studies determined an average in vivo retroperfusion flow rate of ˜35-40 ml/min (for the size of hearts/animals of interest) which was consistent throughout the study. Based on this observed flow rate, and given the arterial temperature of approximately 37° C., the perfusate temperate (temperature at distal tip) was calculated for the MH-SARP catheter (an exemplary perfusion system 100 including a catheter 1000) by benchtop experiment. The catheter was submerged in a 37° C. circulating bath to imitate the venous environment. The perfusate was pumped from the heated bath into the same programmable peltier cooling circuit used for in vivo studies. The effluent was collected and the temperature measured. The bath temperature was also recorded (Fluke 561 IR thermometer). This translated to a decrease in temperature of approximately 11° C. The flow rate was doubled, with minimal impact to the temperature delta demonstrating sufficient cooling capacity. Combined, we had the desired relationship between the cooling circuit, catheter, and subsequent hypothermic distribution within the myocardial layers.

In vivo Validation. The specific aim of validating the efficacy for the SARP+/−MH to reduce infarct size and RI was successfully completed. Swine (n=20) underwent acute coronary artery occlusion for 30 minutes followed by treatment with normothermia retroperfusion, hypothermia retroperfusion, or an additional 30 minutes of occlusion with only the catheter in place and no retroperfusion (sham untreated control). Arterial blood, coronary venous blood, retroperfusion effluent and central venous blood samples were taken to determine effluent oxygen tension, oxygen consumption, glucose uptake, lactate uptake and cardiac troponin.

Echocardiographic measurements were taken from apical 2-chamber and parasternal short axis views of the LV. Other measurements included aortic blood pressure and ECG waveforms. Following baseline measurements, the LAD was occluded distal to the second diagonal branch. Blood samples and echocardiographic measurements were taken at 30 minute intervals post-occlusion in addition to aortic blood pressure and ECG waveforms for ST segment depression and PVC analysis (index of RI). A custom percutaneous temperature probe was placed within the LAD area-at-risk, such that the probe remained at a 3 mm depth from the inner wall of the myocardium. As shown in FIG. 30, the thermocouple was able to detect a notable reduction in subendocardial temperature immediately following the initiation of MH-SARP. The cooling component consisted of an extra-corporeal peltier system between the arterial harvesting sheath and the delivery catheter. This reduced the risk to the patient and cost of the system by significantly reducing the complexity and cost of the one-time use catheter. This also allowed the catheter to be developed for deliverability, insulation, and pressure modulation while minimizing the overall diameter. Animals receiving normothermia were also connected to the cooling circuit but the cooler was not turned on. Perfusion pressure, flow rate, and subendocardial temperatures were recorded continuously. Retroperfusion treatment was terminated at 60 minutes post LAD occlusion by simultaneous deflation of LAD and SARP catheter balloons. Animals were recovered for 4 weeks follow up and blood sampling.

No significant differences in functional endpoints were observed between cohorts. Ejection fraction was modestly reduced from 61.2±1.6%, 59.0±3.1% and 70.3±5.5% at baseline to 55.6±6.3%, 53.7±1.6% and 58.9±3.2% at 4 weeks for control, SARP and MH-SARP, respectively. Observable differences in EF may have been limited by the relatively short recovery period of 4 weeks which will be extended to 8 weeks in the current proposal. Despite having no significant changes in EF, the infarcted area (expressed relative to area at risk) was significantly reduced from 28.1±2.9% in control animals to 4.7±1.6% and 1.9±0.6% in SARP and MH-SARP treated animals, respectively (FIG. 31A). Reductions in infarct size paralleled a decrease in cardiac TnI levels which were significantly reduced at 90 minutes and 2.5 hrs following LAD occlusion (FIG. 31B). The extent of the observed reduction in infarct size is remarkable and unprecedented which is hugely exciting and emphasizes the novelty of the SARP therapeutic approach. Additional functional endpoints were obtained from 2D strain and wall thickness where similar to EF, no differences were observed. The lack of difference in wall thickness following 30 minutes of retroperfusion (SARP or MH-SARP vs. control) as well as at 4 weeks recovery supports that there no interstitial edema occurred during the therapy and consequently no long-term issues were noted. These findings are important for supporting the safety of the auto-retroperfusion approach which serves to minimize exposure to higher pressures (auto-retro) via pressure drop across the catheter that could otherwise occur in the presence of mechanical pumps.

Initiation of MH-SARP produced a rapid cooling of the subendocardium from 35.9±0.3° C. to 35.0±0.2° C. Although only a moderate reduction in temperature was measured, it is important to note that it was measured at the most distal, subendocardial ischemic region to the retroperfusion source (i.e., apical LAD temperature measurement vs. SARP catheter (an exemplary perfusion system 100 including a catheter 1000) placed in the GCV). Hence, the subepicardial and midwall LAD regions experienced a greater reduction in temperature as supported by bench results that identified the relative distributions of MH across regions of the myocardium. Regardless, the rapid reduction in temperature supports effective delivery of retroperfusion therapy which was also confirmed via contrast injection and coronary venogram. Additional validation measurements to assess sufficient retroperfusion were also obtained via placement of a 0.014″ pressure wire through the SARP catheter (an exemplary perfusion system 100 including a catheter 1000) with the sensor located in the vein distal to the catheter tip. Although retroperfusion pressure was elevated relative to baseline (38.1±1.6 vs. 20.9±1.7 mmHg), the magnitude of increase was below the threshold identified for causing edema or hemorrhage (60 mmHg) and is supported by negative gross histological findings (i.e., FIG. 34) which suggest normal myocyte organization. The retroperfusion flow rate for SARP and MH-SARP was 37.3±3.4 and 40.2±1.9 ml/min following 30 minutes of retroperfusion, respectively.

The marked reduction in infarct size and cTnI levels is supported by analysis of ECG ST segment depression, where we observed a significant recovery in the degree of segment depression within 10 min following initiation of therapy (SARP and MH-SARP vs. control, FIG. 32A). The results of ST segment analysis also corresponding with a significant reduction in the number of PVCs (FIG. 32B) and absence of QRS distortion observed during the reperfusion period which are common endpoints for studies evaluating the degree of RI. Hence, our findings support that SARP +/−MH was able to reduce the degree of ischemic and RI. Although no significant difference in myocardial oxygen consumptions was observed (SARP at 240.2±37.2 vs MH-SARP at 253.5±31.5 μl/O₂/ml/min), there was a significant difference in metabolism compared to controls. Following initiation of retroperfusion, an increase in effluent PO₂ was observed (FIG. 33A, taken from great cardiac vein in controls or over the wire LAD balloon in SARP animals; i.e., effluent). This somewhat paradoxical finding suggests a reduced oxygen uptake (arterial PO₂ clamped on medical oxygen) which suggests conversion to a glycolytic mechanism as shown by marked increase in glucose uptake (FIG. 33B). These data demonstrate that the onset of anaerobic glycolysis as evidenced by lactate release across the ischemic bed (FIG. 33C) preserved cell viability which supports staining results for infarct size. IL-1, IL-6 and TNFα assays were negative. Collectively, our data indicate that SARP and MH-SARP preserves cellular integrity and diminishes infarction by conversion to anaerobic glycolysis which limits RI. Although there are differences in known apoptotic markers of RI such as caspase-3 (FIG. 34), no functional differences were observed between SARP and MH-SARP.

Additional validation information is performed as follows.

Animal Preparation

Twenty female Yorkshire domestic swine were divided in three groups, normothermia SARP (n=7), mild hypothermia SARP (n=6), and sham control (n=7), with body weight of 49.2±5.4 kg. The animals were housed at California Medical Innovations Institute-Animal Care Facilities. The pigs had ad libitum access to water and were fed a commercial diet (Teklad 8753). A room temperature of 68-72° F. and humidity of 30% to 70% were maintained. The animals were carefully checked for preexisting diseases and acclimated for a minimum of 3 days before undergoing the interventional procedures. The pigs were fasted overnight. Sedation was achieved with ketamine, 20 mg/kg IM, and surgical anesthesia was maintained with isoflurane 1.5-2.5%. Ventilation with 100% O₂ was provided with a ventilator and maintained PCO₂ at approximately 35 mmHg. Body temperature was kept at 36.0° C.-37.2° C. with a heating pad and a Bair Hugger system. Electrocardiographic (ECG) leads were attached to the animals' limbs and cardiac electrical signals were monitored on a Physio-Control Lifepak 12 monitor/defibrillator and a PowerLab data acquisition system (ADInstruments, Colorado Springs, Colo.) for offline ECG analysis. The analysis was performed using LabChart (ADInstruments, Colorado Springs, Colo.) ECG analysis pre-settings for swine: QRS width 40 ms, R-R waves 200 ms, Pre-P baseline 50 ms, Maximum PR 140 ms, Maximum RT 400 ms, and ST height 60 ms from alignment.

Under sterile conditions, introducer sheaths were percutaneously inserted into the jugular veins and common femoral arteries. Heparin, 100 IU/kg IV, was administered before instrumentation and was then supplemented with 5,000 IU every hour. The left anterior descending (LAD) artery was accessed using a percutaneous femoral approach. A 3-mm Maverick over-the-wire balloon catheter (Boston Scientific, Marlborough, Mass.) was inserted through the right femoral artery and positioned under fluoroscopic guidance into the LAD artery, distal to the second diagonal branch.

The temperature of the subendocardium was measured via a sterile custom percutaneous temperature probe comprised of a 5F radial catheter with an 18 gauge needle affixed within the distal tip of the catheter such that 3.5 mm of the needle protruded from the catheter. Before sterilization, a thermocouple was passed through the catheter and the tip of the thermocouple was secured in the bevel of the needle with epoxy. The catheter was sealed on the proximal and distal ends to ensure hemostasis throughout the procedure. The temperature probe was advanced through the left femoral artery into the LV until the catheter was apposed against the myocardial wall within the LAD area at risk, thus ensuring a 3.5 mm measurement depth. The temperature measurement was determined via a data acquisition system and recorded via LabChart (ADInstruments, Colorado Springs, Colo.). The baseline temperature was recorded prior to initiation of therapy. A representative experimental tracing recorded from the subendocardial temperature probe is shown in FIG. 30

The SARP catheter was inserted through the right jugular vein, advanced into the coronary sinus, and positioned at the junction of the great cardiac and LAD veins. With all catheters in place, baseline measurements (echocardiography, blood sample collection, arterial pressure and ECG recording) were taken before initiation of the procedure.

Mild Hypothermia-Selective Autoretroperfusion (MH-SARP) System

The system was comprised of an arterial access sheath, an extracorporeal Peltier cooling system used in conjunction with a stainless steel heat transfer heat exchanger, an inline drug delivery port, a flow control mechanism, and the custom delivery SARP catheter. The catheter was similar to an Ansel I sheath with a custom proximal fitting to facilitate blood flow, and a compliant balloon on the distal section of the catheter to ensure occlusion of the great cardiac vein in order to avoid back flow towards the coronary sinus during SARP therapy. These components were interconnected via luer-to-barb fittings and silicone tubing. Arterial blood, shunted from the right carotid artery, passed via silicone tubing through the heat exchanger, and was then delivered to the LAD vein (including the drug delivery port and flow control mechanism) connected to the SARP catheter. The arterial blood was delivered into the LAD vein using the animal's own pulse pressure (i.e., autoretroperfusion) without the need of synchronized pumps.

In all three groups, the LAD artery was occluded for 60 min and then reperfused for 30 min. The control group received no treatment. In the normothermia SARP and mild hypothermia SARP groups, therapy was initiated following 30 min of LAD artery occlusion, and instituted for 30 min while the artery remained occluded. To assess the effect of therapy on longer ischemic periods, in one SARP animal we occluded the LAD artery for 90 min and instituted SARP at 60 min post-occlusion. In one sham control animal, on the other hand, we reduced the occlusion period to 30 min, followed by reperfusion. These two additional animals were not considered in the analysis.

The heart was defibrillated if fibrillation occurred during the occlusion period. Ventricular arrhythmias during occlusion were managed with Lidocaine, 1-1.5 mg/kg IV and Amiodarone, 0.5 mg/min IV. After the procedure, the animals received antibiotics and painkillers, and were followed-up for 4 weeks.

Echocardiography

Two-dimensional transesophageal and transthoracic echocardiograms were obtained in all animals using an iE33 ultrasound system (Philips, Andover, Mass.) for serial measurements of LV function. Long and short axes views were obtained during the surgical procedure at 30-min intervals and analyzed offline to determine LV volumes, ejection fraction (EF), and wall thickness using QLAB 10.5 (Philips, Andover, Mass.). Additional echocardiograms were obtained every two weeks. Blood Sample Collection

Arterial blood, coronary venous blood, central venous blood, and retroperfusion effluent blood samples were collected every 30 min to determine metabolic parameters including oxygen tension, glucose uptake, lactate uptake, and cardiac troponin I (cTnI) levels. miR-1 and miR-133a levels were measured in plasma. The retroperfusion effluent samples were obtained via the lumen of the LAD balloon catheter while inflated.

Reverse Transcription and Quantitative Real Time PCR Analysis

MicroRNA (miRNA or miR) assays were performed as described previously (21). Plasma was mixed with TRIzol LS (Invitrogen, Carlsbad, Calif., USA) in a 1:3 ratio and the samples were homogenized by vortexing >30 s. RNA was then isolated using an miRNeasy mini kit (Qiagen, Hilden, Germany) according to the manufacturer's instructions. Reverse transcription and quantitative PCR (qPCR) were performed using the TaqMan@ microRNA assay Kit (Applied Biosystems) as previously described (22, 23). Briefly, reverse transcription was performed in a 15 μL reaction mix containing 20 ng of total RNA, 3 μL of miRNA primer mix, 1 mM dNTP, 50 U reverse transcriptase, and 3.8 u RNase inhibitor. Reactions were incubated at 16° C. for 30 min, 42° C. for 30 min, and 85° C. for 5 min. PCR was performed in a 10 μL reaction volume containing 0.5 μL of miRNA primer and TaqMan probe mix, 0.67 μL of RT product (five-fold dilution), and 5 μL of TaqMan Universal PCR Master Mix. The cycling conditions were as follows: 10 min at 95° C., followed by 40 cycles of 15 s at 95° C. and 1 min at 60° C. miR-16 was used as an internal control. For all samples, reverse transcription and qPCR were performed three times and qPCR was performed in triplicate. Relative gene expression levels between baseline and 90 min samples were determined using the comparative Ct (2^(−ΔΔCt)) method after normalizing to miR-16. The baseline values were normalized to 1.

Heart Preparation

After four weeks of the initial interventional procedure, the heart was arrested in diastole with a saturated solution of potassium chloride injected through the jugular vein, excised and transported to the lab in 0.9% sodium chloride. Transmural biopsy samples were taken from different regions of the LV for histological analysis. The LAD artery was cannulated with tygon tubing at the site where the balloon catheter was inflated during the SARP procedure. The myocardium was double-stained with Evans blue and 2,3,5-triphenyltetrazolium chloride (TTC) for demarcation of the area at risk and the infarcted area (24). The heart was perfused with 10 mL of 1% Evans blue. The ascending aorta and pulmonary artery were removed, as well as the atria and the right ventricle. The LV was then cut into 8 slices (˜10 mm thick) from apex to base (parallel to the atrioventricular groove). The slices were further stained with 1% TTC at 37° C., fixed in 10% buffered formalin, and scanned for determination of infarct size relative to the area at risk using ImageJ software.

Statistical Analysis

All statistical analyses were performed using SigmaStat 3.5 (Systat Software, Point Richmond, Calif.). The data were expressed as mean±SD, unless otherwise specified. The differences between the various parameters and groups were evaluated using analysis of variance (ANOVA) and Student's t-test. The differences were considered significant at p<0.05.

Results

The hemodynamic parameters in the control, normothermia and hypothermia groups at baseline, occlusion, retroperfusion, and reperfusion periods are summarized in Table 1.

TABLE 1 Hemodynamic Parameters Control Normothermia Hypothermia Baseline Systolic BP (mmHg) 81.1 ± 7.5  84.2 ± 8.4 81.4 ± 7.0 Diastolic BP (mmHg) 53.6 ± 8.0  58.1 ± 11.4 53.9 ± 8.1 MAP (mmHg) 66.1 ± 8.4  70.6 ± 10.6 65.3 ± 7.3 Heart Rate (bpm) 85.4 ± 11.9  85.7 ± 26.8 95.3 ± 31.8 Pulse Pressure (mmHg) 27.5 ± 2.8  26.1 ± 5.1 27.5 ± 6.2 Ischemia Systolic BP mmHg) 61.5 ± 5.9³  65.8 ± 11.7² 59.3 ± 4.1³ Diastolic BP (mmHg) 46.8 ± 6.0³  48.0 ± 10.3 42.4 ± 5.2 MAP (mmHg) 54.1 ± 6.4²  55.7 ± 12.1¹ 49.7 ± 5.1² Heart Rate (bpm) 85.2 ± 10.1  88.6 ± 26.1 95.9 ± 17.0 Pulse Pressure (mmHg) 14.7 ± 2.0³  7.9 ± 2.7² 17.0 ± 2.5² Retroperfusion Systolic BP (mmHg)  65.5 ± 7.1² 59.1 ± 5.0³ Diastolic BP (mmHg)  48.6 ± 7.2 43.5 ± 5.1 MAP (mmHg)  56.3 ± 7.7² 50.4 ± 5.4³ Heart Rate (bpm)  86.9 ± 14.9 98.8 ± 14.8 Pulse Pressure (mmHg)  16.8 ± 1.7 15.6 ± 2.2 Reperfusion Systolic BP (mmHg) 51.7 ± 7.8³  67.5 ± 6.9^(2, 5) 70.5 ± 5.8^(1, 6) Diastolic BP (mmHg) 34.4 ± 9.5²  46.3 ± 8.3⁴ 44.8 ± 6.2⁴ MAP (mmHg) 42.3 ± 8.9³  54.8 ± 8.1^(3, 4) 54.4 ± 6.3^(1, 4) Heart Rate (bpm) 78.0 ± 17.1 105.6 ± 36.7 97.5 ± 14.7⁴ Pulse Pressure (mmHg) 17.3 ± 2.8³  21.2 ± 5.2 25.7 ± 4.4⁵ ¹p < 0.05, ²p < 0.01, ³p < 0.001 relative to baseline values. ⁴p < 0.05, ⁵p < 0.01, ⁶p < 0.001 relative to control group. BP, blood pressure. MAP, mean arterial pressure.

In all 3 groups, the systolic and mean arterial pressure (MAP) significantly decreased during occlusion, retroperfusion and reperfusion compared with their corresponding baseline values. Systolic pressure and MAP during reperfusion, however, were significantly higher in the normothermia and hypothermia groups than the control group. Similarly, in the control group, pulse pressure significantly decreased during occlusion and reperfusion. In the normothermia and hypothermia groups, pulse pressure also significantly decreased during occlusion, remained approximately the same during retroperfusion, but returned to almost baseline levels during reperfusion. Compared with controls, the hypothermia group showed a significantly higher pulse pressure during reperfusion. Heart rate remained comparable in all 3 groups under different conditions relative to baseline values. During the reperfusion period, however, the hypothermia group showed significant increase in heart rate compared with the control group.

Following the initiation of MH-SARP in the corresponding animal group, the myocardial temperature in the subendocardium decreased approximately one degree Celsius (35.9° C.±0.3° C. to 35.0° C.±0.2° C.) in less than 4 min, as shown in FIG. 30. Once MH-SARP treatment was terminated at 60 min post LAD occlusion, the subendocardial temperature progressively increased to baseline levels in approximately 15 min (FIG. 30).

No significant differences in LV function were observed between groups at the end of the study. EF was modestly reduced from 61.2%±2.7%, 59.0%±8.2%, and 58.6%±4.5% at baseline to 58.0%±10.1%, 53.7%±4.0%, and 58.9%±7.8% at 4 weeks for control, normothermia, and hypothermia groups, respectively.

The analysis of ECG ST-segment deviation demonstrated significant recovery in the degree of segment depression within 10 min following initiation of therapy (SARP and MH-SARP vs. control, p<0.05, FIG. 32A). Significant reduction in the number of arrhythmic events (FIG. 32B) and absence of QRS distortion during the reperfusion period were also observed with SARP and MH-SARP (p<0.05).

Cardiac troponin levels in the control, normothermia, and hypothermia groups are shown in FIG. 31B. Significant reduction in cTnI levels was observed at 90 min and 2.5 hours following LAD occlusion with SARP (4.4±3.5 ng/mL, p<0.05 and 16.8±16.0 ng/mL, p<0.01) and MH-SARP (1.4±0.8 ng/mL, p<0.01 and 8.1±6.8 ng/mL, p<0.001) vs. control (14.2±9.0 ng/mL and 42.6±13.5 ng/mL).

The levels of miR-1 (FIG. 35A) and miR-133a (FIG. 35B), novel biomarkers of reperfusion injury, were measured in blood plasma. A seven-fold increase in miR-1 after reperfusion was observed in the control group compared to baseline (p<0.04). In the normothermia and hypothermia groups, the values decrease to three and four times of those of baseline values, respectively, but the difference were not significant. Similarly, miR-133a in the control group also increased seven times after reperfusion, compared to the baseline levels (p<0.02). In the normothermia group, miR-133a also increased approximately seven times at 90 min, although the values were not statistically different to baseline. In the hypothermia group, the values between baseline and 90 min were nearly identical.

A reduction in infarct size (relative to the area at risk) was observed with SARP (83.2%) and MH-SARP (93.3%) relative to control (FIG. 31A). The infarcted area decreased from 28.1%±7.7% [median 27.1% (quartiles 1-3, 25.5-29.6%)] in the control group to 4.7%±4.0% [median 3.9% (quartiles 1-3, 1.7-9.0%)] in the normothermia group (p=0.0001) and 1.9%±1.4% [median 1.8% (quartiles 1-3, 0.8-3.2%)] in the hypothermia group (p=0.0001). No significant differences were found between SARP and MH-SARP (p=0.15). The 1 pilot animal with 90 min LAD occlusion and 30 min SARP treatment showed similar infarcted area (0.7%) to the normothermia group animals (0% to 9.9%). On the other hand, the 1 pilot control animal with 30 min occlusion followed by reperfusion also showed similar infarcted area (22.5%) to the rest of the animals in the control group (16.8% to 42.8%). FIG. 35C shows myocardial sections obtained from approximately the same regions in the control, normothermia, and hypothermia groups, double-stained with Evans blue and TTC. The infarcted area (white) is clearly demarcated in the control group (left panel) vs. normothermia (central panel) and hypothermia (right panel) groups.

FIG. 34 shows representative histological myocardial sections stained for the RI marker caspase-3. Caspase-3 expression was elevated in control (subsection B) specimens, compared with SARP (subsection C) and MH-SARP (subsection D) samples, which approximate healthy viable myocardium (subsection A).

Indices of cardiac metabolism in response to SARP and MH-SARP are shown in FIGS. 33A, 33B, and 33C. PO₂ levels measured from effluent samples (FIG. 33A) in the control group remained almost the same at 30 and 60 min of occlusion (18.1±3.9 mmHg and 19.8±2.7 mmHg, respectively) compared with baseline levels (18.0±4.6 mmHg). In the normothermia group, PO₂ levels increased from 17.8±1.5 mmHg at baseline to 35.2±5.5 mmHg (p<0.01) and 28.6±9.0 mmHg after 5 and 30 min of SARP, respectively. Similarly, PO₂ levels in the hypothermia group increased from 20.8±3.7 mmHg at baseline to 28.3±4.1 mmHg after 5 min of MH-SARP and 27.0±1.6 mmHg after 30 min of MH-SARP. The values between normothermia and control groups were significantly different after 5 (p<0.01) and 30 (p<0.01) min of therapy, respectively. In the hypothermia group significance was found after 30 min of therapy (p<0.01) when compared with control. FIG. 33B shows glucose uptake measured from effluent samples. Within 5 min of SARP, glucose uptake increased to 24.0±2.1 mg/dL (p<0.01), and after 30 min to 18.0±3.3 mg/dL compared with baseline values (8.4±4.7 mg/dL) in the normothermia group. In the hypothermia group, the values were 28.0±3.4 mg/dL (p<0.01) and 20.2±4.0 mg/dL after 5 and 30 min of MH-SARP, respectively, compared with 9.7±9.2 mg/dL at baseline. Glucose uptake in the normothermia (p<0.01) and hypothermia (p<0.01) groups was significantly higher than the control group after 5 minutes of treatment. FIG. 33C shows lactate uptake measurements from effluent samples. After 5 min of SARP, lactate uptake significantly decreased from 0.4±0.2 mmol/L (baseline) to −4.4±2.0 mmol/L in the normothermia group (p<0.01). After 30 min of SARP, lactate uptake was −1.5±0.6 mmol/L (p<0.001). Similarly, in the hypothermia group, lactate uptake significantly decreased from 0.6±0.4 mmol/L at baseline to −2.6±1.3 mmol/L after 5 min of MH-SARP, and to −1.4±0.8 mmol/L after 30 min of MH-SARP. The values in the normothermia and hypothermia groups were significantly different after 5 (p<0.01, p<0.01) and 30 (p<0.001, p<0.05) min of treatment, respectively, compared with the control group.

We have shown for the first time that selective autoretroperfusion, alone or in combination with mild hypothermia, significantly reduces myocardial infarct size up to 98% in a swine model of acute myocardial infarction. MH-SARP was remarkably effective in reducing myocardial infarct size [98.1±1.4% (93.3% relative to control)], with concomitant attenuation of markers for myocardial ischemia (cTnI), reperfusion injury (degree of ST-segment depression), and cardiomyocyte injury (oxygen, glucose and lactate uptake, as well as caspase-3 expression). Moreover, SARP alone was also able to significantly reduce infarct size [95.3±4.0% (83.2% relative to control)] and all associated indices to near equivalent levels without the complexity of hypothermia.

Several animal and clinical studies have documented the beneficial effects of hypothermia to minimize myocardial reperfusion injury following AMI. Similarly, the beneficial effects of coronary venous retroperfusion for the ischemic myocardium, with and without synchronized pumping have been largely investigated. In the present study, we sought to evaluate the adjunctive therapeutic effects of both autoretroperfusion (without the use of synchronized pumps) and mild hypothermia to prevent the deleterious effects of myocardial reperfusion following PCI post-acute coronary occlusion. We used the animals' own pulse pressure to retroperfuse arterial blood through the coronary venous system. We also chose a large animal model (swine) of myocardial ischemia to minimize the variability in infarct size and maintain translational relevance.

Employing the animals' own pulse pressure, arterial blood from the carotid was rapidly cooled down using an extracorporeal cooling system and then retroperfused through the coronary venous system without the need for external pumps. Furthermore, with the use of regional hypothermia instead of whole body hypothermia, we avoided hemodynamic deterioration and other adverse effects such as shivering. Subendocardial temperature was reduced by approximately one degree Celsius in <4 min following initiation of therapy. This small reduction in temperature provided an additive protective effect to SARP (95.3±4% to 98.1±1.4% infarct size reduction), salvaging the ischemic myocardium from irreversible damage. The remarkable reduction in infarct size observed in the present study is likely the combined effects of blood supply reaching the ischemic area, removal of adverse metabolites (retroperfusion), and reduction in cellular metabolism (hypothermia), i.e., positively affecting the oxygen supply-demand relation. The rapid decrease in subendocardial temperature also supports the effective delivery of SARP, which in this case, was confirmed via contrast injection and coronary venogram. Furthermore, measurement of the retroperfusion pressure (38.1±1.6 mmHg during therapy vs. 20.9±1.7 mmHg at baseline) in the LAD vein, distal to the tip of the SARP catheter, indicated that we achieved an ideal pressure (<50 mmHg), necessary to avoid myocardial edema and hemorrhage. Previous studies evaluating the effects of machine-driven synchronized hypothermic retroperfusion in dogs also reported a significant decrease in myocardial infarct size although not to the magnitude reported in the present study. It is very interesting that autoretroperfusion appears to confer greater benefit than machine-retroperfusion. In their study, Wakida and colleagues reported an infarct size (relative to the area at risk) of 6.2±3.3% in dogs treated with hypothermic retroperfusion, and 24.1±6.7% with normothermic retroperfusion. Synchronized retroperfusion only permits myocardial retro flow in diastole and venous drainage during systole. The heart, however, is capable of distributing the blood flow of the ischemic myocardium once blood is delivered through the coronary venous system, facilitating at the same time the wash out of toxic products without the need of intermittent occlusion of the coronary sinus. The presence of intervenous connections is important for the distribution of flow to different regions of the myocardium, minimizing the damage that buildup of intravascular pressure may cause.

Along with the significant reduction in infarct size, MH-SARP and SARP alone significantly reduced the incidence of ventricular arrhythmias during the reperfusion period, which correlated with outcome in humans. The presence of arrhythmias has been attributed to attenuation of conduction, which usually occurs during ischemia and is pre-requisite for re-entry. Recently, it has been postulated that mild hypothermia prevents ischemia-induced conduction block and conduction velocity slowing by preserving gap junction coupling as well as sodium channel function. It is worth mentioning that large myocardial temperature gradients can cause severe arrhythmias due to the dispersion of the action potential, which underscores the importance of the degree of hypothermia as an adjunctive therapy of myocardial ischemia. An approximate 1° C. reduction of the subendocardial temperature significantly reduced the incidence of arrhythmic events during the reperfusion period. SARP alone also significantly reduced the presence of arrhythmic events, although to a lesser degree (7.3±5.0 vs. 5.5±1.3).

Following the initiation of SARP, an increase in effluent PO₂ was observed. This somewhat paradoxical finding suggests a reduced oxygen uptake, which may be the result of cell death or conversion to a glycolytic ischemic metabolism. Support for the latter is provided by marked increase in glucose uptake. These data demonstrate that the onset of anaerobic glycolysis, as evidenced by lactate release across the ischemic bed, may have contributed to the preservation of cell viability. Our main hypothesis was that mild hypothermia induces a decrease in metabolic demand and hence reduces myocardial cell death during the reperfusion period. The results obtained in this study with SARP alone, however, suggest that the primary benefit may be derived by oxygen delivery to the ischemic myocardium and removal of toxic byproducts.

Although we did not find significant differences in EF, the low levels of cTnI in the MH-SARP and SARP alone groups suggest cardiomyocyte preservation. Troponins are regulatory proteins integral to myocardial contraction. The observed differences in EF may have been limited by the relatively short recovery period of four weeks.

Two biomarkers of myocardial infarction and reperfusion injury, miRNA-1 and miRNA-133a, were strongly upregulated in plasma from the control group. This upregulation of miRNAs in plasma is likely due to release from the cytoplasm of cardiac cells. On the other hand, non-significant upregulation of miRNA-1 and miRNA-133a was found with implementation of SARP alone or MH-SARP before reperfusion.

The data indicate that SARP and MH-SARP preserve cellular integrity and decrease myocardial infarct size.

While various embodiments of retroperfusion devices and systems along with regional mild hypothermia and methods for using the same have been described in considerable detail herein, the embodiments are merely offered by way of non-limiting examples of the disclosure described herein. It will therefore be understood that various changes and modifications may be made, and equivalents may be substituted for elements thereof, without departing from the scope of the disclosure. Indeed, this disclosure is not intended to be exhaustive or to limit the scope of the disclosure.

Further, in describing representative embodiments, the present disclosure may have presented a method and/or a process as a particular sequence of steps. However, to the extent that the method or process does not rely on the particular order of steps set forth therein, the method or process should not be limited to the particular sequence of steps described, as other sequences of steps may be possible. Therefore, the particular order of the steps disclosed herein should not be construed as limitations of the present disclosure. In addition, disclosure directed to a method and/or process should not be limited to the performance of their steps in the order written. Such sequences may be varied and still remain within the scope of the present disclosure. 

1. A connector for use with an autoretroperfusion and hypothermia system, comprising: a blood lumen inlet, a blood lumen outlet, and a blood lumen extending therebetween; a coolant inlet for receiving a cooling product; a reservoir for receiving the cooling product from the coolant inlet and cooling a blood flowing through the blood lumen; and a coolant outlet for receiving the cooling product from the reservoir and sending the cooling product out of the connector.
 2. The connector of claim 1, wherein blood flowing through the blood lumen is pumped solely by a patient's own heart.
 3. The connector of claim 1, wherein the blood lumen is defined within the reservoir
 4. The connector of claim 1, wherein the reservoir is immediately adjacent the blood lumen.
 5. The connector of claim 1, wherein the blood lumen inlet and the coolant inlet are positioned at a first end of the connector; and the blood lumen outlet and the coolant outlet are positioned at a second end of the connector such that the cooling product and the blood flowing through the blood lumen flow in a parallel direction.
 6. The connector of claim 1, further comprising a noncontact temperature sensor at the blood lumen outlet to determine the temperature of blood leaving the connector.
 7. The connector of claim 1, wherein the cooling product is at a cooled temperature before entering the coolant inlet.
 8. The connector of claim 1, wherein the blood lumen inlet and the blood lumen outlet comprise luer lock connections.
 9. The connector of claim 1, wherein the connector comprises a 6 French diameter and 30 cm long flexible tubing.
 10. A connector for use with an autoretroperfusion and hypothermia system, comprising: a blood lumen inlet for receiving a patient's blood and a coolant inlet for receiving a cooling product, wherein the blood lumen inlet and the coolant inlet are positioned at a first end of the connector; a reservoir for receiving the cooling product from the coolant inlet; a blood lumen outlet and a coolant outlet for receiving the cooling product from the reservoir, wherein the blood lumen out and the coolant outlet are positioned at a second end of the connector; and a blood lumen defined within the reservoir and extending between the blood lumen inlet and the blood lumen outlet.
 11. The connector of claim 10, further comprising a noncontact temperature sensor at the blood lumen outlet to determine the temperature of blood leaving the connector.
 12. The connector of claim 10, further comprising the patient's flowing blood within the blood lumen wherein the blood flows through the blood lumen without use of an outside pump.
 13. A method of using a connector as part of an autoretroperfusion and hypothermia system comprising the steps of: introducing a patient's blood and a cooling product into a first end of the connector; flowing the blood and cooling product through the connector wherein the cooling product cools the blood; and allowing the cooled blood and cooling product to exit a second end of the connector.
 14. The method of claim 11, wherein the blood flows through the connector solely under the power of the patient's own heart.
 15. The method of claim 11, further comprising the step of cooling the cooling product before the step of introducing the patient's blood and the cooling product at the first end of the connector.
 16. The method of claim 11, further comprising the step of measuring a temperature of the blood at the second end of the connector without contacting the blood.
 17. The method of claim 16, further comprising the step of adjusting the temperature of the cooling product based on the measured temperature of blood.
 18. The method of claim 11, wherein the blood exiting the connector at the second end of the connector exits at a pressure less than 50 mmHg.
 19. The method of claim 11, further comprising the steps of: connecting an arterial blood source at the first end of the connector; connecting a catheter at the second end of the connector; and wherein the patient's blood flows from the arterial blood source, through the connector, and into the catheter.
 20. The method of claim 19, further comprising the step of connecting a cooling system at the coolant inlet and the coolant outlet and using the cooling system to cool the cooling product. 